Next Article in Journal
A Comparative Study of Melittins from Apis florea and Apis mellifera as Cytotoxic Agents Against Non-Small Cell Lung Cancer (NSCLC) Cells and Their Combination with Gefitinib
Previous Article in Journal
Therapeutic Effects of Pharmacological Modulation of Serotonin Brain System in Human Patients and Animal Models of Fragile X Syndrome
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 26
Issue 6
10.3390/ijms26062494
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Contribution of Human Antimicrobial Peptides to Fungi

by
Qiaoxi Zhang
,
Kitman Choi
,
Xiaoyue Wang
,
Liyan Xi
and
Sha Lu
*
Department of Dermatology and Venereology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, #107 Yanjiang West Rd., Guangzhou 510120, China
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(6), 2494; https://doi.org/10.3390/ijms26062494
Submission received: 5 February 2025 / Revised: 7 March 2025 / Accepted: 8 March 2025 / Published: 11 March 2025
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Versions Notes

Abstract

:
Various species of fungi can be detected in the environment and within the human body, many of which may become pathogenic under specific conditions, leading to various forms of fungal infections. Antimicrobial peptides (AMPs) are evolutionarily ancient components of the immune response that are quickly induced in response to infections with many pathogens in almost all tissues. There is a wide range of AMP classes in humans, many of which exhibit broad-spectrum antimicrobial function. This review provides a comprehensive overview of the mechanisms of action of AMPs, their distribution in the human body, and their antifungal activity against a range of both common and rare clinical fungal pathogens. It also discusses the current research status of promising novel antifungal strategies, highlighting the challenges that must be overcome in the development of these therapies. The hope is that antimicrobial peptides, as a class of antimicrobial agents, will soon progress through large-scale clinical trials and be implemented in clinical practice, offering new treatment options for patients suffering from infections.

1. Introduction

Fungi are delicate and ubiquitous organisms that play a crucial role in complex ecosystems. Fungal infections represent a significant public health concern for human health [1]. These infections can lead to two major types of diseases: superficial fungal diseases and invasive or systemic infections. The impact ranges from superficial infections that affect quality of life to systemic involvement that can be life-threatening. Recent global estimates indicate that approximately 6.5 million cases of invasive fungal infections occur each year, leading to 3.8 million deaths, with around 2.5 million (68%) of these deaths directly attributable to fungal infections [2,3,4]. Specifically, diseases such as invasive aspergillosis, Candida bloodstream infections, Pneumocystis pneumonia, and cryptococcal meningitis exhibit significant incidence and mortality rates. For example, the annual incidence of Candida bloodstream infections is approximately 1.56 million, with a mortality rate of 63.6% [4]. These fungal infections not only pose a major threat to global public health but also impose a heavy burden on healthcare resources and economic systems. The treatment of these infections often requires expensive antifungal medications and prolonged hospital stays, further exacerbating the socio-economic burden.
However, clinical practice relies on just three main classes of antifungal drugs—azoles, polyenes, and echinocandins—while additional agents like 5-flucytosine are used as adjuncts [5,6,7]. The limited range of these drugs, combined with their widespread use, has facilitated the emergence of drug-resistant strains of Candida, Cryptococcus, and Aspergillus. Moreover, in the past three decades, only one new class of antifungal agents has been introduced, leaving many common invasive fungal infections, including those caused by resistant strains, inadequately treated [8,9,10,11,12]. This clearly highlights that the development of antifungal drugs has not kept pace with the growing clinical demand. The high mortality rates associated with invasive fungal infections, the need for prolonged treatment courses, and the narrow spectrum of action and cross-resistance among existing antifungals all underscore the urgent need for innovation [13,14,15]. There is a critical demand for safer treatments with reduced toxicity, as well as novel antifungal agents with improved efficacy. Improving the accessibility of fungal infection treatment options and developing effective preventive measures are crucial strategies to alleviate the global burden and economic pressure associated with these infections.
AMPs are small proteins found in many organisms that target and inhibit the growth of microorganisms, including bacteria, fungi, and viruses [16,17,18]. As of January 2024, the Antimicrobial Peptide Database (APD) contains 3940 AMPs, with 2463 of them derived from animals [19]. This number is expected to continue rising. AMPs are a key part of the innate immune system and serve as the first line of defense against pathogens [20,21,22,23,24]. These peptides are naturally produced by a variety of organisms, including plants, animals, and microbes [25,26]. Because of their evolutionary conservation, many AMPs share similarities across different species, including mammals and humans. Numerous antimicrobial peptides from plants and other sources have been shown to exhibit strong antifungal properties. For example, bCp12A, an AMP derived from hydrolyzed casein in buffalo milk, demonstrates significant antimicrobial activity against Staphylococcus aureus and could be used to control bacterial contamination in milk, with potential applications in agriculture and food safety [27,28]. In a 2023 study, the antimicrobial peptide CB-M was found to have direct antifungal activity against gray mold and also helped induce resistance to gray mold in cherry tomato fruit [29]. Likewise, human AMPs are being progressively identified for their effectiveness against a broad spectrum of fungi. In this review, we have discussed the role of human AMPs in the treatment of fungal infections.

2. Human Antimicrobial Peptides

Human AMPs are found throughout the human body, including in organs like the skin, respiratory tract, and digestive system, as well as in immune cells and bodily fluids such as saliva, tears, and breast milk [30,31,32,33]. The classification of human AMPs currently lacks a standardized system. The most widely adopted approach categorizes AMPs based on their peptide family, including defensins, transferrins, and histones. Alternative classification schemes exist based on functional specificity (antibacterial, antifungal, or antiviral activity) or anatomical distribution (production sites or localization within the human body). The combination of the GEO transcriptome database with existing studies has provided new insights into the expressional levels and functions of human AMPs [34,35]. The distribution and concentration of these peptides often correspond to the types of local pathogens. For instance, Histatin 5 is present at much higher levels in human saliva than in sweat or on the skin, where it plays an important role in fighting bacteria that cause dental cavities and certain Candida species, helping prevent oral thrush in individuals with healthy immune systems [36,37].
For some AMPs that are constantly expressed, their levels can change based on other factors. For example, the expression of defensins in the endometrium varies with different stages of the menstrual cycle and in response to microbial infections [38,39,40]. These peptides are a key part of the body’s natural defense system, with broad-spectrum antimicrobial activity against bacteria, fungi, viruses, and even some cancer cells [41,42,43,44,45]. In addition, the antimicrobial peptide database includes peptides that aid in wound healing, reduce inflammation, and have potential anti-diabetic effects.
In summary, AMPs are becoming increasingly recognized for their diverse roles in immune defense, thanks to their widespread presence and evolutionarily conserved structures. Many human AMPs also show antifungal activity, making them promising candidates for developing new antibiotics and other treatments.

3. Antifungal Activities of Human AMPs

A wide range of AMPs have been identified so far. In humans, the main families of AMPs include defensins, cathelicidins, transferrin (LF), and histones (Hst). Lysozyme, the first human AMP to be discovered, was found in nasal secretions [46,47]. While lysozyme mainly targets the bacterial cell wall component peptidoglycan, its activity against fungi and viruses is relatively weak. LL-37, the only known human member of the cathelicidins family, exhibits antifungal properties against several common fungal pathogens, such as Candida and Aspergillus.
These peptides show varying levels of activity, and Table 1 summarizes the human AMPs currently known and their antifungal properties. Research on the antifungal effects of AMPs has primarily focused on their in vitro antimicrobial activity, stability, hemolytic toxicity, and efficacy in animal models. With the advancement of peptide engineering, many researchers have modified natural AMPs through truncation or chemical modification, or synthesized entirely new peptides using amino acid-based chemical synthesis. Synthetic peptide design based on natural AMP templates focuses on two strategic goals: first, the identification and enhancement of bioactive motifs essential for antimicrobial function; second, the systematic removal or modification of sequence regions contributing to cytotoxicity and proteolytic instability [48]. This dual-focused strategy facilitates the creation of next-generation antimicrobial agents with optimized therapeutic potential. For instance, rational modification of the PvD1 γ-core sequence, including charge optimization and length reduction, yielded the γ33-41 PvD1 ++ peptide. This nine-amino acid derivative showed enhanced antifungal activity and represents a promising candidate for developing cost-effective antifungal therapeutics [49,50].
Despite the growing interest in human AMPs, their stability in vivo remains a relatively underexplored aspect. Although a significant number of AMPs have been discovered and characterized, many remain unidentified, highlighting the ongoing significance of human peptidome research for future scientific advancements [51]. In the following sections, this review will examine the antifungal effects of AMPs on fungi responsible for superficial infections, as well as those causing systemic infections, with a focus on recent research advancements in these areas.
Table 1. Human AMPs currently known and their antifungal properties.
Table 1. Human AMPs currently known and their antifungal properties.
Antimicrobial PeptideSource (Human)Antifungal ActivityReference
Lactoferrin (LF)Mucosal secretions, saliva, milkCandida albicans, Candida kefyr, Candida krusei, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus[52,53,54,55,56]
Histatin-5 (Hst 5)SalivaCandida albicans, Candida kefyr, Candida, Candida parapsilosis, Cryptococcus neoformans, fumigatus[57,58,59,60,61,62,63,64,65]
Histatin-1 (Hst 1)Oral cavityCandida albicans, Candida krusei[66]
(Hst 2)Oral cavityCandida albicans, Candida krusei[66,67]
Ribonuclease A (RNase A)Vertebrates, chromosome 14Candida albicans, Candida tropicalis[68,69,70]
RNase 1PancreasCandida albicans, Candida tropicalis[69,71]
RNase 2EosinophilsCandida albicans, Candida tropicalis[70]
RNase 5 (Angiogenin)NeurotoxinCandida albicans, Candida tropicalis[72]
RNase 7SkinCandida albicans, Candida tropicalis, Aspergillus fumigatus[73,74,75]
Dermcidin (DCD)Sweat glandsStaphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Enterococcus faecalis, Candida albicans[76,77,78]
LL-37Airways, oral cavity, tongue, esophagus, epididymis, small intestineCandida albicans, Candida kefyr, Candida krusei, Candida parapsilosis, Cryptococcus neoformans, fumigatus, Trichophyton rubrum, Microsporum canis[79,80,81,82,83,84,85,86,87]
HepcidinLiverCandida albicans, Candida tropicalis, Aspergillus fumigatus[88,89,90,91,92]
Vasostatin-1Endocrine, neuroendocrine, and neuronal cellsCandida albicans, Candida tropicalis, Candida kefyr, Aspergillus fumigatus, Fusarium solani, Sporothrix schenckii[93]
Alpha-defensins (HD5, HD6)Intestinal Paneth cells, neutrophilsCandida albicans, Aspergillus fumigatus, Candida glabrata, Cryptococcus neoformans[94,95,96,97]
Beta-defensins (hBD-1, hBD-2, hBD-3)Epithelial cells (skin, respiratory tract, urogenital tract)Candida albicans, Candida glabrata, Aspergillus fumigatus, Cryptococcus neoformans, Trichophyton rubrum[98,99,100,101,102,103,104,105,106,107,108,109,110]

3.1. Malassezia

Malassezia is a lipophilic yeast that is commonly found on the surface of human skin [111,112]. A study using high-throughput sequencing to investigate the microbiomes of the forehead, scalp, and arms of healthy individuals found that the relative abundance of Malassezia species was significantly higher than that of other fungal taxa [113,114]. Overgrowth of Malassezia can lead to conditions such as tinea versicolor and Malassezia folliculitis and is also closely associated with skin disorders like seborrheic dermatitis and atopic dermatitis. A case-control study revealed that several human defensins (e.g., β-defensin 2, β-defensin 3, LL-37, S100A7, and RNase 7) were significantly elevated in patients with tinea versicolor, suggesting that the expression of these AMPs is linked to Malassezia infection [115]. Two forms of the cathelicidin peptide, LL-37 in human neutrophils and CRAMP in murine neutrophils, have been shown to inhibit the growth of Malassezia species, with minimum inhibitory concentrations (MICs) ranging from 20 to 30 μM [115,116]. Additionally, another study demonstrated that a peptide analogous to frog skin secretion, P5, and a peptide derived from recombinant antibody constant regions exhibited effective antimicrobial activity against Malassezia furfur.
However, it has also been observed that in patients with eczema, the secretion of LL-37 correlates with the severity of inflammation triggered by Malassezia infection. This suggests that the immunomodulatory effects induced by LL-37 may also play a role in the pathogenesis of eczema. As a result, further research is needed to better understand the interactions between fungal pathogens and AMPs, particularly in the context of skin conditions. Additionally, the development of new synthetic AMPs should take into account their potential immunomodulatory effects. Achieving a balance between antimicrobial activity and the modulation of inflammatory responses in both in vivo and in vitro studies is essential for advancing the clinical application of AMPs.

3.2. Trichophyton

Trichophyton species are important pathogens responsible for superficial skin infections and/or infections of its appendages, such as tinea corporis, tinea pedis, onychomycosis, and others [117,118]. Infected areas typically present with symptoms such as pruritus and desquamation [118,119]. The most commonly isolated species in clinical settings include Trichophyton rubrum, along with other species like T. mentagrophytes, Microsporum canis, and Epidermophyton floccosum [120]. Studies [116,121] have shown that the expression of cathelicidin peptides is upregulated in skin biopsies from patients diagnosed with tinea pedis and tinea corporis. In vitro experiments have also demonstrated that exposure to T. rubrum induced an increase in the expression of mRNA encoding AMPs in keratinocytes [116].
While most dermatophyte infections are not directly life-threatening, the concern worldwide about the increasing resistance of dermatophytes to standard antifungal treatments is growing [122,123,124,125]. Trichophyton indotineae, a strain within the T. mentagrophytes/T. interdigitale complex, has recently emerged as a drug-resistant pathogen [125,126]. On the other hand, the lengthy treatment courses required for onychomycosis often lead to poor patient adherence, reducing treatment effectiveness and lowering cure rates.
In this context, AMPs offer a promising alternative, potentially overcoming the limitations of current therapies [2,59]. Over the past two decades, research on AMPs targeting dermatophytes has intensified. One such AMP, the cathelicidin-like peptide Pa-MAP [121], which is rich in alanine analogs, exhibits effective antifungal activity against both T. mentagrophytes and T. rubrum. Similarly, a lactoferrin-derived peptide, Compound 5, has demonstrated superior antifungal effects in human onychomycosis models, outperforming commonly used antifungal agents like terbinafine and amorolfine [127,128,129]. Currently, the cyclic heptapeptide Novexatin is undergoing clinical trials for the treatment of onychomycosis [130,131]. Undoubtedly, human AMPs such as LL-37, human β-defensins, and RNase 7 hold significant potential as therapeutic agents for skin fungal infections [132,133,134,135,136,137,138].
In addition to the aforementioned human-derived AMPs, natural cyclic heptapeptides isolated from the marine bacterium Stylissa caribica and the synthetic cyclopolypeptide 8 have also shown antifungal activity against dermatophytes like T. mentagrophytes and T. rubrum (MIC 6 µg/mL) [139,140,141]. A cyclic peptide, Phaeofungin, derived from algae, has demonstrated antifungal activity against T. mentagrophytes (MIC 4 µg/mL). These findings suggest that cyclic structures may play a role in combating superficial infections caused by dermatophytes such as tinea pedis and tinea unguium. A recent genomic analysis of skin fungal pathogens (Trichophyton, Microsporum) revealed an enrichment of LysM-containing domains, which could serve as binding regions for cyclic heptapeptides [140,142,143,144]. Notably, a limitation of current research is lacking the studies investigating the specific binding sites and conformations of AMPs in Trichophyton species, which may hinder accurate predictions of how structural modifications affect antimicrobial efficacy.

3.3. Candida

Candida species are integral to the human microbiome, playing a key role in the structure and metabolic functions of microbial communities. As we know, Candida species can colonize superficial areas such as the oral mucosa, conjunctiva, and skin, leading to conditions like intertrigo and oral thrush [145,146,147,148,149]. Candida can be also detected in gastric and fecal samples, suggesting its presence in the gastrointestinal tract, although it remains unclear whether this represents transient colonization or long-term persistence.
In the past two decades, Candida infections have emerged as a major public health issue [150,151]. In the United States, Candida is the fourth leading cause of hospital-acquired bloodstream infections, with a mortality rate as high as 40% [152]. More seriously, Candida can invade the bloodstream, causing systemic infections across various organs [153,154]. These severe infections predominantly occur in immunocompromised patients, such as those on long-term immunosuppressive therapy or with HIV [155,156,157]. In addition, due to the limited range of antifungal drugs available for clinical use, there has been a decline in the sensitivity of C. albicans to azoles, and C. auris has shown multidrug resistance to various antifungal agents [158,159].
As a result, researchers are actively seeking new therapeutic strategies to combat Candida infections. AMPs are among the first molecules released by mucosal surfaces and are integral components of the innate immune response against fungal infections. Extensive research has shown that AMPs possess potent antifungal activity against Candida species, and their mechanisms of action are well understood. The ADP3 database alone records 910 AMPs with antifungal activity against Candida species. In 1994, dermaseptin I, extracted from frog skin, was the first AMP identified to exhibit antifungal activity against C. albicans in vitro [160,161]. AMPs with anti-Candida properties are widely distributed across diverse biological taxa. Representative examples include NaD1 from Nicotiana alata flowers and Gomesin from Acanthoscurria gomesiana [162,163]. Although the current repertoire of human-derived anti-Candida peptides is less extensive compared to those from insects and arachnids, significant progress has been made in characterizing human AMPs such as Psoriasin and β-defensin [164,165]. In addition, recent studies have progressively revealed the therapeutic value of modified human AMP derivatives in combating Candida infections. The human AMP family exhibits an intriguing pattern of structural homology with subtle variations among its members [166,167]. These naturally occurring variations offer a promising foundation for developing enhanced peptide-based therapeutics through structural modification approaches.
Subsequent studies have focused on the in vitro and in vivo antifungal activities of various AMPs, including human defensins (e.g., HBD-6, LL-37), lysozyme, and histone family peptides, all of which have shown effective antifungal properties against Candida species [30,168,169,170,171,172,173,174,175]. In experimental protocols, researchers commonly employ azole antifungal agents and melittin as positive controls [176]. The most representative MIC values are typically selected for subsequent mechanistic investigations and structural optimization studies. Due to the diverse range of diseases caused by Candida, in vivo models have been extensively developed to study the efficacy of AMPs. These include local skin infection models, corneal infection models, and systemic infection models in mice, which evaluate the impact of specific AMPs on overall survival and organ-specific fungal burden [177,178,179,180]. These critical animal experiments are indispensable for validating both the safety parameters and pharmacological efficacy of AMPs in clinical applications, necessitating strict protocol compliance to maximize therapeutic potential [181].
In addition to the well-studied AMPs, researchers have been exploring other potential antimicrobial peptides derived from human tissues. For example, a peptide fragment (2–2) of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), isolated from human placenta, was found to enter Candida cells and induce apoptosis [182]. In 2023, a peptide, YY (PYY (1–6)), was discovered in human intestinal epithelial Paneth cells, offering a new approach for the packaging and delivery of antimicrobial peptides [183]. Furthermore, α-melanocyte-stimulating hormone (α-MSH), secreted by the skin, has been shown to reduce the viability of C. albicans and inhibit its hyphal formation [184,185,186].
However, these newly discovered peptides were not initially identified for their antifungal activity and may have other physiological roles. For instance, GAPDH is an essential enzyme in the glycolytic pathway, and α-MSH plays a regulatory role in various hormones, including growth factors, insulin, and aldosterone [182,186,187,188,189]. S100A7, an AMP secreted by human keratinocytes, demonstrates limited direct fungicidal activity against Candida species, but it exhibits significant antibiofilm properties [190]. This protein facilitates the disruption of fungal biofilms, thereby enhancing the penetration and efficacy of conventional antifungal agents [191]. These characteristics position S100A7 as a promising candidate for future combination therapies in the treatment of Candida infections. To develop these peptides as potential antifungal agents, it is crucial to balance their antifungal efficacy with their other biological activities to minimize potential side effects and adverse reactions.

3.4. Aspergillus

Aspergillus infections are the second most common fungal infections that lead to hospitalization, following those by Candida species [192,193,194,195]. The most common mode of infection is the inhalation of conidia from the air. Epidemiological data have identified several high-risk populations, particularly individuals with pre-existing pulmonary conditions such as chronic obstructive pulmonary disease (COPD), asthma, or cystic fibrosis, as well as those recovering from severe respiratory viral infections, including influenza and COVID-19 [193,196,197].
Among pathogenic Aspergillus species, A. fumigatus is the most prevalent in the environment and the most commonly implicated in clinical aspergillosis, followed by A. niger [198,199,200,201]. Studies have shown that in patients with chronic sinusitis complicated by A. fumigatus infection, the expression levels of LL-37 are upregulated. An in vitro study demonstrated that LL-37 inhibits the hyphal growth of A. fumigatus in a dose-dependent manner after 12 h of incubation [81]. In addition to LL-37, other common human antimicrobial peptides, such as human β-defensin (hBD) and lactoferrin, have also shown effective antifungal activity against A. fumigatus [56,202,203,204]. The antimicrobial efficacy of AMPs against Aspergillus species is influenced by multiple factors, including peptide concentration, fungal strain characteristics, the growth phase of the organism, and environmental conditions. These variables collectively determine the outcome of AMP-Aspergillus interactions and subsequent antifungal activity. On another hand, the host immune response to Aspergillus infection is significantly modulated by AMPs, which activate key immune effector cells such as neutrophils, macrophages, and dendritic cells. This activation enhances fungal pattern recognition and promotes phagocytic elimination of Aspergillus conidia and hyphae, thereby strengthening the host’s antifungal defense mechanisms [205].
Future research is needed for developing more diverse in vivo models to validate the in vivo efficacy and potential clinical applications of human antimicrobial peptides against Aspergillus species.

3.5. Cryptococcus

Like other fungi, many antimicrobial peptides have been shown to exhibit activity against Cryptococcus in vitro [206,207,208]. For example, a proline-rich peptide (2733 Da) isolated from a pig parotid gland extract demonstrated antifungal activity against clinical isolates of Cryptococcus neoformans, with an EC50 value of 2.2 μM [209].
However, unlike other fungi, Cryptococcus is a common cause of meningitis in clinical settings, often leading to a range of neurological and psychiatric symptoms in affected patients [208,210,211,212]. Currently, amphotericin B (AmB) is the most commonly used treatment for fungal-induced central nervous system infections [208,210]. Global guidelines suggest that both AmB deoxycholate (AmB–) and lipid formulations of AmB can be used as adjuncts to intravenous therapy. This highlights the critical role of lipophilicity in drug design, as it facilitates the drug’s passage across the blood–brain barrier to reach the therapeutic site.
Given the generally hydrophilic nature of antimicrobial peptides and the lipophilic characteristics of the blood–brain barrier, a 2010 study proposed several strategies to enhance the delivery of AmB to the brain, such as increasing the dosage, intrathecal injection, and using brain-targeted peptide-modified liposomes. In vitro experiments demonstrated that a self-assembled, cationic nanoparticle composed of a lipophilic cholesterol conjugate with a TAT peptide sequence (G3R6TAT) exhibited good antifungal activity against Cryptococcus growth, slightly surpassing that of AmB [213,214]. Additionally, in a meningitis rabbit model, this nanoparticle improved survival rates [214]. These findings provide evidence that this nanoparticle formulation effectively inhibits Cryptococcus growth and inflammatory responses in both cerebrospinal fluid and brain parenchyma.

3.6. Histoplasma capsulatum

Histoplasma capsulatum is typically found in the feces of birds and bats, and humans usually contract histoplasmosis through airborne inhalation of its spores. As a result, the primary site of fungal infection is commonly the lungs [215,216,217]. However, in immunocompromised individuals, such as patients with HIV/AIDS, the infection can disseminate through the bloodstream to other organs, including the skin, bone marrow, brain, liver, spleen, and lymphatic system, leading to progressive disseminated histoplasmosis.
In in vitro studies, mouse macrophages that produce human defensins have been shown to effectively inhibit the replication of H. capsulatum within cells, thus controlling the spread of the infection [218]. Additionally, a member of the human heat shock protein 60 (HSP60) family, HIS-62, has been found to offer protective effects against pulmonary histoplasmosis in mice [219].
Furthermore, some newly synthesized antimicrobial peptides, such as Lys-Nva-FMDP, have demonstrated the ability to inhibit the growth of H. capsulatum in its yeast form, as well as exhibit promising in vivo antifungal activity in organ load tests in mice [220,221]. These novel synthetic peptides, with clearly defined structures, were designed based on the structural and functional studies of natural antimicrobial peptides [221,222,223,224]. Due to their purpose-driven synthesis, the antifungal mechanisms of these artificially synthesized peptides are more clearly understood.

3.7. Paracoccidioides brasiliensis

Paracoccidioides brasiliensis is a dimorphic fungus capable of causing disease in both healthy and immunocompromised hosts [225]. The risk of developing disseminated paracoccidioidomycosis is particularly high in immunocompromised individuals. Research on peptides involved in P. brasiliensis infection in humans has largely focused on the infection process itself [226,227,228,229]. WI-1 is a surface protein found on P. brasiliensis cells that has been shown to significantly induce inflammatory responses in human paracoccidioidomycosis, serving as a target antigen for cell-mediated immunity in this disease [230,231,232]. Such target antigens, by synthesizing similar structures that preserve their antigenicity while reducing their toxicity, present an ideal candidate for antimicrobial peptide-based vaccines.

3.8. Mucorales

Several fungi from the order Mucorales can cause mucormycosis in humans, a severe infection that can affect multiple organ systems [233,234,235,236,237,238]. These fungi include species from the genera Mucor, Rhizopus, or Rhizomucor species [239,240,241]. The most common sites of infection are the nasal and cerebral regions, as well as the lungs [242]. Mucormycosis is most commonly observed in immunocompromised patients, individuals with poorly controlled diabetes (especially those with diabetic ketoacidosis), and patients receiving iron chelation therapy with deferoxamine [242,243,244]. Among these, Rhizopus is the most frequent causative agent of mucormycosis. Mortality rates are higher in patients with prolonged neutropenia, disseminated disease, or brain infections [245].
Research on Rhizopus primarily focuses on the structure, active sites, and key amino acids of enzymes such as Rhizopus aspartic proteinases, lipases, and glucosidases, which play significant roles in fungal virulence [246,247,248,249,250,251,252,253,254]. However, there is limited research on the hemolytic toxicity and cell-killing effects of Rhizopus, and no animal studies have been conducted to explore the potential of reducing fungal loads in Rhizopus infections [254,255,256,257,258]. This gap in research may be attributed to the challenges in constructing appropriate animal models for Rhizopus infection.
Recent studies, however, have identified newly synthesized peptides with effective antifungal activity against Mucorales. One such peptide inhibitor binds to the aspartic proteinase of Rhizopus, impacting its catalytic activity and thereby exerting antifungal effects [259]. This direction of research, focused on protein–protein interactions, is somewhat distinct from other fungal studies but shows promise [259,260]. Additionally, a study synthesized an antimicrobial undecapeptide with spore-killing activity, demonstrating its potential to control apple rot [261]. This progress highlights the faster pace of development in agricultural and food-related applications of antifungal peptides compared to that of clinical medical research [262,263].

3.9. Talaromyces marneffei

T. marneffei is one of the most important pathogenic thermally dimorphic fungi in China and Southeast Asia [264,265,266,267,268]. The prevalence of HIV/AIDS, particularly in China and other Southeast Asian countries, has led to T. marneffei infections becoming a significant opportunistic infection in AIDS patients [265,269,270,271]. Research on AMPs targeting T. marneffei is limited. The MP1 gene of T. marneffei appears to share similarities with the AFMP1 gene expressed by Aspergillus fumigatus. Therefore, engineering peptides that target AFMP1 may have potential therapeutic effects in controlling T. marneffei infections [272,273].

4. Mechanism by Human AMPs Activity

AMPs are considered promising broad-spectrum antimicrobial agents due to their lack of drug resistance, and their mechanisms of action have been extensively studied [274,275]. Unlike traditional antibiotics, AMPs possess unique structural features that enable them to interact electrostatically with fungal cell membranes, reducing the likelihood of resistance development [276,277,278]. While the exact antifungal mechanisms of AMPs are not fully understood, most of these peptides target fungal cell membranes. Several factors, including charge (cationic or anionic), size, amino acid sequence, conformation, hydrophobicity, and amphipathicity, can influence the activity and mechanism of AMPs. For instance, structural modification of HBD-1 through disulfide bond reduction enables the peptide to acquire antimicrobial activity against C. albicans [279].
In contrast to conventional antifungal agents that typically target single cellular components, AMPs primarily exert their effects through two main mechanisms: direct killing and immune modulation [280,281]. The direct killing mechanism can be further divided into membrane-targeted and non-membrane-targeted actions. Membrane-targeting peptides, such as defensins and LL-37, disrupt the membrane integrity by forming transient pores [282,283,284,285]. These membrane-targeting mechanisms can be explained by various models, including the barrel-stave model, carpet model, pore-forming model, and detergent model [286,287,288,289]. The oligomerization of peptides leads to alterations in the fungal cell membrane, causing leakage of cellular contents and ultimately leading to cell death [290]. Using LL-37 as an illustrative example, this multifunctional antimicrobial peptide induces C. albicans apoptosis through multiple mechanisms. As a pore-forming peptide, it creates membrane pores at nanomolar concentrations, leading to ion efflux and membrane destabilization [291,292]. Following cellular internalization, LL-37 interacts with intracellular targets while simultaneously stimulating endogenous ROS production, which contributes to mitochondrial membrane potential dissipation, a hallmark of apoptotic initiation [293]. The subsequent release of Ca2+ from the endoplasmic reticulum and its mitochondrial translocation further exacerbates organelle dysfunction [294]. Ultimately, cytochrome c release from mitochondria into the cytosol activates caspase proteases, executing the apoptotic cascade. Non-membrane-targeting peptides, such as pleurocidin, pyrrhocidin, and mersacidin, penetrate the cell membrane without directly disrupting it. Chromogranin A (CGA)-N46 exerts its antifungal activity by damaging the mitochondria, inducing vacuolization inside of the yeast cells, disturbing the nuclear envelope and inhibiting DNA synthesis by preventing DNA polymerase action. Instead, they interfere with critical intracellular processes, ultimately resulting in cell death [295,296,297,298].
In addition to their direct antimicrobial activity, AMPs also play a key role in immune modulation by regulating various signaling pathways [299,300,301,302]. They can recruit effector cells, such as phagocytes, to enhance both intracellular and extracellular killing. AMPs also promote macrophage differentiation and dendritic cell maturation through activation of immune cells, stimulation of immune cell proliferation, and the promotion of immunoglobulin and cytokine secretion such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6. Specifically, LL-37 upregulates the expression of aryl hydrocarbon receptor (AHR) and retinoic acid-related orphan receptor γt (RORγt), while simultaneously enhancing the phosphorylation of Smad 2/3 and signal transducer and activator of transcription 3 (STAT3) proteins. These molecular events collectively drive the differentiation of native T cells toward the Th17 phenotype, which plays crucial roles in mucosal immunity and pathogen clearance [303]. Additionally, AMPs also exhibit additional biological functions for the regulation of wound healing processes. Those multifunctional capabilities contribute to tissue homeostasis and cellular turnover, highlighting the diverse physiological roles of AMPs in maintaining organismal integrity [304,305,306].
The diverse mechanisms of AMPs naturally lead to the hypothesis that combining peptides with complementary modes of action may yield synergistic effects. Given the evolutionary conservation of AMPs across species, researchers have focused on exploring combinations of human-derived and non-human AMPs. A notable example is the synergistic interaction between human LL-37 and plant-derived NaD1, which collectively enhance hyphal permeabilization and accelerate fungal cell death [307]. This strategy of leveraging complementary advantages from human and non-human peptides may unlock novel therapeutic options for combating multidrug-resistant fungal infections.
The therapeutic potential of human antimicrobial peptides for fungal infections shares conceptual similarities with vaccine development. Current clinical trial data indicate that topical AMP applications are generally well-tolerated, with few reported adverse events [308]. In preclinical studies examining systemic administration, AMPs have shown manageable cytotoxicity profiles in animal models. Engineered AMP variants and peptides from non-human sources, when designed with precise target specificity, typically demonstrate minimal effects on human cells [180]. Nevertheless, researchers must consider that as natural components of innate immunity, AMPs possess biological activities that extend beyond antifungal action, potentially including mechanisms that could affect normal cellular functions.

5. Sources and Modification of New Antifungal Agents

AMPs can be derived from animals, plants, and microorganisms, or they can be chemically synthesized [26,309,310,311,312]. AMP discovery has evolved through two distinct methodological paradigms. The traditional approach, grounded in the empirical screening of biological peptide libraries, systematically evaluates antimicrobial potential through iterative experimentation. Modern computational strategies, enabled by advances in bioinformatics, now allow for predictive identification of antimicrobial sequences directly from proteomic and genomic datasets. The primary methods for obtaining AMPs include direct isolation from natural sources, heterologous expression, and chemical synthesis. Direct isolation from natural sources involves a combination of solvent extraction, chromatography, and analytical techniques. Chemical synthesis, including solid-phase synthesis, is also commonly employed [313,314]. Among these, chemical synthesis and recombinant production provide reliable, cost-effective means of producing AMPs with high efficiency.
Dissatisfied with the existing AMPs, researchers continue to identify novel AMPs. In terms of direct isolation, advances in sequencing technologies and AI-driven deep learning systems are increasingly used to predict and isolate potential AMPs from biological sources [34,315,316]. For example, one innovative study utilized multiple natural language processing models to successfully identify AMPs with antimicrobial potential from the human gut microbiome [317].
In synthetic AMP development, some synthesized peptide analogs exhibit broader activity against target organisms compared to their natural counterparts. As a result, peptide engineering has emerged as a key area of focus, involving the molecular design and modification of peptides to improve their antimicrobial activity or reduce toxicity. Techniques such as the synthesis of dendrimeric peptides and the cyclization of polypeptides have shown promise in enhancing antifungal activity [318,319,320]. Additionally, positively charged peptides rich in lysine have been associated with reduced toxicity and increased antifungal effectiveness, and could even been used to create sites that bind to nanoparticles to facilitate their delivery [321,322,323,324,325,326,327]. This paradigm shift introduces new scientific considerations, particularly in source organism selection. Microbial communities have emerged as particularly promising discovery platforms, offering three distinct advantages: (1) unparalleled genetic diversity within their collective genomes, (2) evolutionary adaptations shaped by persistent host–microbe interactions, and (3) competitive pressures driving antimicrobial innovation [328,329,330,331,332]. These inherent biological features position microbial ecosystems as rich, largely untapped reservoirs of AMPs with significant translational potential. Overall, peptide engineering relies on a precise understanding of peptide primary and secondary structures, a process that is closely linked to computational methods [333,334]. We anticipate that future advancements in peptide modification strategies will provide more effective options for novel antifungal drugs.

6. Future Directions

Current research on AMPs focuses primarily on their effects on pathogens and their potential applications. Studies are generally divided into in vitro experiments, in vivo experiments, and mechanistic investigations [335]. Regarding fungi, in vitro research typically includes determining the MIC of AMPs against various clinical isolates to evaluate their antimicrobial activity. Additionally, AMPs’ stability under extreme conditions, such as high salinity, extreme pH, or in the presence of proteases, is tested to determine their potential in vivo applicability. Mechanistic studies are also mainly conducted in vitro, often focusing on comparing the expression of various inflammatory factors to understand the immune-modulatory effects of AMPs and their involvement in downstream signaling pathways. Researchers also use techniques such as electron microscopy to visually capture changes in fungal cells after AMP treatment. As previously mentioned, most human AMPs (e.g., HBD, LL-37) induce fungal cell death through membrane interactions, leading to membrane disruption and nuclear envelope dissolution, phenomena observable under electron microscopy. However, these methods are no longer novel. Currently, there is a greater interest in directly confirming molecular interactions after membrane binding, rather than relying on models to hypothesize these interactions.
In vivo studies are less common and mainly focus on Candida species. This is likely due to the diverse infection sites of Candida (e.g., corneal, vaginal, skin, and systemic infections), with superficial localized infection models being much easier to establish than systemic infection models [336,337,338]. Unfortunately, many fungi that cause fatal infections, such as Microsporum and Mucor, have not been studied with regard to the establishment of infection models. It is clear that there is still a long way to go in discovering novel clinical treatments for these fungi. Large-scale clinical trials are also essential for the approval of new drugs. Unlike infections such as influenza or COVID-19, systemic fungal infections are relatively rare, making such trials both costly and difficult to conduct [339]. A promising approach is to conduct small-scale studies initially, followed by the development of an international platform for adaptive clinical trial design, where data can be aggregated and analyzed through meta-analysis.

7. Conclusions

AMPs represent a fascinating and diverse class of molecules with vast potential for treating infections, particularly in an era where antimicrobial resistance is becoming an increasingly urgent problem. These peptides are naturally occurring across various organisms. They have evolved to perform multiple functions, from directly killing pathogens to modulating immune responses. One of the most compelling advantages of AMPs is their effectiveness against resistant fungi, including species of Candida, Aspergillus, and Talaromyces, which have become significant threats, especially in immunocompromised populations. This broad-spectrum antifungal activity, coupled with their rapid action, makes AMPs promising candidates in the fight against infections that are increasingly difficult to treat with conventional antifungal drugs. However, while their potential is immense, there are significant hurdles to overcome before AMPs can be widely used in clinical settings.
First, their stability in vivo remains a major challenge. AMPs are often rapidly degraded in the body, limiting their therapeutic potential. Additionally, their high cost of production and potential toxicity, especially at higher concentrations, require careful optimization. As with many promising therapeutic candidates, the clinical use of AMPs hinges on balancing their antimicrobial potency with safety and patient tolerance.
Furthermore, while we have a growing understanding of the mechanisms through which AMPs combat pathogens, there is still much to learn about their precise interactions with different microorganisms. For instance, the role of AMPs in modulating the immune system, particularly in the context of inflammatory diseases or fungal infections, remains underexplored. Given the complexity of the immune response, AMPs’ dual roles—both as antimicrobial agents and immune modulators—need further investigation to ensure their efficacy and safety in long-term treatments.
In conclusion, while AMPs hold great promise, their path to clinical use will require ongoing research. With continued advancements in peptide engineering and deeper insights into their mechanisms of action, AMPs may one day become a cornerstone of the treatment for fungal infections and other microbial diseases, offering a much-needed alternative to current therapies.

Author Contributions

Q.Z.: Writing—original draft. K.C.: Data curation. X.W.: Methodology. S.L: Validation. L.X.: Writing—review and editing. S.L.: Writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This work was funded by National Natural Science Foundation of China (NSFC, grant number: 82172289).

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Iliev, I.D.; Brown, G.D.; Bacher, P.; Gaffen, S.L.; Heitman, J.; Klein, B.S.; Lionakis, M.S. Focus on fungi. Cell 2024, 187, 5121–5127. [Google Scholar] [CrossRef] [PubMed]
  2. Denning, D.W. Global incidence and mortality of severe fungal disease. Lancet Infect. Dis. 2024, 24, e428–e438. [Google Scholar] [CrossRef] [PubMed]
  3. Suleyman, G.; Alangaden, G.J. Nosocomial Fungal Infections: Epidemiology, Infection Control, and Prevention. Infect. Dis. Clin. N. Am. 2021, 35, 1027–1053. [Google Scholar] [CrossRef] [PubMed]
  4. Köhler, J.R.; Hube, B.; Puccia, R.; Casadevall, A.; Perfect, J.R. Fungi that Infect Humans. Microbiol. Spectr. 2017, 5, 10-1128. [Google Scholar] [CrossRef]
  5. Perlin, D.S.; Rautemaa-Richardson, R.; Alastruey-Izquierdo, A. The global problem of antifungal resistance: Prevalence, mechanisms, and management. Lancet Infect. Dis. 2017, 17, e383–e392. [Google Scholar] [CrossRef]
  6. Perlin, D.S. Cell Wall-Modifying Antifungal Drugs. Curr. Top. Microbiol. Immunol. 2020, 425, 255–275. [Google Scholar] [CrossRef]
  7. Robbins, N.; Wright, G.D.; Cowen, L.E. Antifungal Drugs: The Current Armamentarium and Development of New Agents. Microbiol. Spectr. 2016, 4, 10–1128. [Google Scholar] [CrossRef]
  8. Ben-Ami, R.; Kontoyiannis, D.P. Resistance to Antifungal Drugs. Infect. Dis. Clin. N. Am. 2021, 35, 279–311. [Google Scholar] [CrossRef]
  9. Fisher, M.C.; Hawkins, N.J.; Sanglard, D.; Gurr, S.J. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 2018, 360, 739–742. [Google Scholar] [CrossRef]
  10. Pristov, K.E.; Ghannoum, M.A. Resistance of Candida to azoles and echinocandins worldwide. Clin. Microbiol. Infect. 2019, 25, 792–798. [Google Scholar] [CrossRef]
  11. Dannaoui, E. Antifungal resistance in mucorales. Int. J. Antimicrob. Agents 2017, 50, 617–621. [Google Scholar] [CrossRef] [PubMed]
  12. Carlet, J.; Collignon, P.; Goldmann, D.; Goossens, H.; Gyssens, I.C.; Harbarth, S.; Jarlier, V.; Levy, S.B.; N’Doye, B.; Pittet, D.; et al. Society’s failure to protect a precious resource: Antibiotics. Lancet 2011, 378, 369–371. [Google Scholar] [CrossRef] [PubMed]
  13. Kovács, R.; Mahmoudi, S. Editorial: Alternative approaches to antifungal drugs against drug-resistant fungi. Front. Cell. Infect. Microbiol. 2023, 13, 1184922. [Google Scholar] [CrossRef] [PubMed]
  14. Jampilek, J. Novel avenues for identification of new antifungal drugs and current challenges. Expert Opin. Drug Discov. 2022, 17, 949–968. [Google Scholar] [CrossRef]
  15. Vanzolini, T.; Magnani, M. Old and new strategies in therapy and diagnosis against fungal infections. Appl. Microbiol. Biotechnol. 2024, 108, 147. [Google Scholar] [CrossRef]
  16. van Hoek, M.L. Antimicrobial peptides in reptiles. Pharmaceuticals 2014, 7, 723–753. [Google Scholar] [CrossRef]
  17. Lehrer, R.I.; Ganz, T. Antimicrobial peptides in mammalian and insect host defence. Curr. Opin. Immunol. 1999, 11, 23–27. [Google Scholar] [CrossRef]
  18. Lomakin, I.B.; Gagnon, M.G.; Steitz, T.A. Antimicrobial peptides targeting bacterial ribosome. Oncotarget 2015, 6, 18744–18745. [Google Scholar] [CrossRef]
  19. Wang, G.; Li, X.; Wang, Z. APD3: The antimicrobial peptide database as a tool for research and education. Nucleic Acids Res. 2016, 44, D1087–D1093. [Google Scholar] [CrossRef]
  20. Jirillo, E.; Magrone, T. Editorial: Antimicrobial Peptides as Mediators of Innate Immunity. Curr. Pharm. Des. 2018, 24, 1041–1042. [Google Scholar] [CrossRef]
  21. Zhou, H.; Wu, S.; Liu, L.; Li, R.; Jin, P.; Li, S. Drosophila Relish Activating lncRNA-CR33942 Transcription Facilitates Antimicrobial Peptide Expression in Imd Innate Immune Response. Front. Immunol. 2022, 13, 905899. [Google Scholar] [CrossRef] [PubMed]
  22. Drago-Serrano, M.E.; Campos-Rodriguez, R.; Carrero, J.C.; de la Garza, M. Lactoferrin and Peptide-derivatives: Antimicrobial Agents with Potential Use in Nonspecific Immunity Modulation. Curr. Pharm. Des. 2018, 24, 1067–1078. [Google Scholar] [CrossRef] [PubMed]
  23. Kang, H.K.; Lee, H.H.; Seo, C.H.; Park, Y. Antimicrobial and Immunomodulatory Properties and Applications of Marine-Derived Proteins and Peptides. Mar. Drugs 2019, 17, 350. [Google Scholar] [CrossRef] [PubMed]
  24. Brogden, K.A.; Ackermann, M.; McCray, P.B., Jr.; Tack, B.F. Antimicrobial peptides in animals and their role in host defences. Int. J. Antimicrob. Agents 2003, 22, 465–478. [Google Scholar] [CrossRef]
  25. Bruno, R.; Maresca, M.; Canaan, S.; Cavalier, J.F.; Mabrouk, K.; Boidin-Wichlacz, C.; Olleik, H.; Zeppilli, D.; Brodin, P.; Massol, F.; et al. Worms’ Antimicrobial Peptides. Mar. Drugs 2019, 17, 512. [Google Scholar] [CrossRef]
  26. García-Beltrán, J.M.; Arizcun, M.; Chaves-Pozo, E. Antimicrobial Peptides from Photosynthetic Marine Organisms with Potential Application in Aquaculture. Mar. Drugs 2023, 21, 290. [Google Scholar] [CrossRef]
  27. Shi, Y.; Li, Y.; Yang, K.; Wei, G.; Huang, A. A novel milk-derived peptide effectively inhibits Staphylococcus aureus: Interferes with cell wall synthesis, peptidoglycan biosynthesis disruption reaction mechanism, and its application in real milk system. Food Control 2023, 144, 109374. [Google Scholar] [CrossRef]
  28. Hernández-Aristizábal, I.; Ocampo-Ibáñez, I.D. Antimicrobial Peptides with Antibacterial Activity against Vancomycin-Resistant Staphylococcus aureus Strains: Classification, Structures, and Mechanisms of Action. Int. J. Mol. Sci. 2021, 22, 7927. [Google Scholar] [CrossRef]
  29. Yang, X.; Wang, Y.; Jiang, H.; Song, R.; Liu, Y.; Guo, H.; Meng, D. Antimicrobial peptide CB-M exhibits direct antifungal activity against Botrytis cinerea and induces disease resistance to gray mold in cherry tomato fruit. Postharvest Biol. Technol. 2023, 196, 112184. [Google Scholar] [CrossRef]
  30. De Smet, K.; Contreras, R. Human antimicrobial peptides: Defensins, cathelicidins and histatins. Biotechnol. Lett. 2005, 27, 1337–1347. [Google Scholar] [CrossRef]
  31. Liepke, C.; Baxmann, S.; Heine, C.; Breithaupt, N.; Ständker, L.; Forssmann, W.G. Human hemoglobin-derived peptides exhibit antimicrobial activity: A class of host defense peptides. J. Chromatogr. B 2003, 791, 345–356. [Google Scholar] [CrossRef] [PubMed]
  32. Perinpanayagam, H.E.; Van Wuyckhuyse, B.C.; Ji, Z.S.; Tabak, L.A. Characterization of low-molecular-weight peptides in human parotid saliva. J. Dent. Res. 1995, 74, 345–350. [Google Scholar] [CrossRef] [PubMed]
  33. Shaban, S.; Patel, M.; Ahmad, A. Fungicidal activity of human antimicrobial peptides and their synergistic interaction with common antifungals against multidrug-resistant Candida auris. Int. Microbiol. Off. J. Span. Soc. Microbiol. 2023, 26, 165–177. [Google Scholar] [CrossRef] [PubMed]
  34. Santos-Júnior, C.D.; Torres, M.D.T.; Duan, Y.; Rodríguez Del Río, Á.; Schmidt, T.S.B.; Chong, H.; Fullam, A.; Kuhn, M.; Zhu, C.; Houseman, A.; et al. Discovery of antimicrobial peptides in the global microbiome with machine learning. Cell 2024, 187, 3761–3778.e3716. [Google Scholar] [CrossRef]
  35. Wang, G.; Vaisman, I.I.; van Hoek, M.L. Machine Learning Prediction of Antimicrobial Peptides. Methods Mol. Biol. 2022, 2405, 1–37. [Google Scholar] [CrossRef]
  36. Torres, P.; Díaz, J.; Arce, M.; Silva, P.; Mendoza, P.; Lois, P.; Molina-Berríos, A.; Owen, G.I.; Palma, V.; Torres, V.A. The salivary peptide histatin-1 promotes endothelial cell adhesion, migration, and angiogenesis. FASEB J. 2017, 31, 4946–4958. [Google Scholar] [CrossRef]
  37. Torres, S.R.; Garzino-Demo, A.; Meiller, T.F.; Meeks, V.; Jabra-Rizk, M.A. Salivary histatin-5 and oral fungal colonisation in HIV+ individuals. Mycoses 2009, 52, 11–15. [Google Scholar] [CrossRef]
  38. Sørensen, O.E.; Borregaard, N.; Cole, A.M. Antimicrobial peptides in innate immune responses. Contrib. Microbiol. 2008, 15, 61–77. [Google Scholar] [CrossRef]
  39. Huttner, K.M.; Bevins, C.L. Antimicrobial peptides as mediators of epithelial host defense. Pediatr. Res. 1999, 45, 785–794. [Google Scholar] [CrossRef]
  40. Lyu, W.; Curtis, A.R.; Sunkara, L.T.; Zhang, G. Transcriptional Regulation of Antimicrobial Host Defense Peptides. Curr. Protein Pept. Sci. 2015, 16, 672–679. [Google Scholar] [CrossRef]
  41. Kovalchuk, L.V.; Gankovskaya, L.V.; Gankovskaya, O.A.; Lavrov, V.F. Herpes simplex virus: Treatment with antimicrobial peptides. Adv. Exp. Med. Biol. 2007, 601, 369–376. [Google Scholar] [CrossRef] [PubMed]
  42. Ahmed, A.; Siman-Tov, G.; Hall, G.; Bhalla, N.; Narayanan, A. Human Antimicrobial Peptides as Therapeutics for Viral Infections. Viruses 2019, 11, 704. [Google Scholar] [CrossRef] [PubMed]
  43. Mousavi Maleki, M.S.; Rostamian, M.; Madanchi, H. Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2. Expert Rev. Anti. Infect. Ther. 2021, 19, 1205–1217. [Google Scholar] [CrossRef] [PubMed]
  44. Aghamiri, S.; Zandsalimi, F.; Raee, P.; Abdollahifar, M.A.; Tan, S.C.; Low, T.Y.; Najafi, S.; Ashrafizadeh, M.; Zarrabi, A.; Ghanbarian, H.; et al. Antimicrobial peptides as potential therapeutics for breast cancer. Pharmacol. Res. 2021, 171, 105777. [Google Scholar] [CrossRef]
  45. Tonk, M.; Vilcinskas, A.; Rahnamaeian, M. Insect antimicrobial peptides: Potential tools for the prevention of skin cancer. Appl. Microbiol. Biotechnol. 2016, 100, 7397–7405. [Google Scholar] [CrossRef]
  46. Merlini, G.; Bellotti, V. Lysozyme: A paradigmatic molecule for the investigation of protein structure, function and misfolding. Clin. Chim. Acta; Int. J. Clin. Chem. 2005, 357, 168–172. [Google Scholar] [CrossRef]
  47. Wiesner, J.; Vilcinskas, A. Antimicrobial peptides: The ancient arm of the human immune system. Virulence 2010, 1, 440–464. [Google Scholar] [CrossRef]
  48. Souza, P.F.N.; Marques, L.S.M.; Oliveira, J.T.A.; Lima, P.G.; Dias, L.P.; Neto, N.A.S.; Lopes, F.E.S.; Sousa, J.S.; Silva, A.F.B.; Caneiro, R.F.; et al. Synthetic antimicrobial peptides: From choice of the best sequences to action mechanisms. Biochimie 2020, 175, 132–145. [Google Scholar] [CrossRef]
  49. de Oliveira Mello, É.; Taveira, G.B.; de Oliveira Carvalho, A.; Gomes, V.M. Improved smallest peptides based on positive charge increase of the γ-core motif from PνD(1) and their mechanism of action against Candida species. Int. J. Nanomed. 2019, 14, 407–420. [Google Scholar] [CrossRef]
  50. Mello, E.O.; Ribeiro, S.F.; Carvalho, A.O.; Santos, I.S.; Da Cunha, M.; Santa-Catarina, C.; Gomes, V.M. Antifungal activity of PvD1 defensin involves plasma membrane permeabilization, inhibition of medium acidification, and induction of ROS in fungi cells. Curr. Microbiol. 2011, 62, 1209–1217. [Google Scholar] [CrossRef]
  51. Bosso, M.; Ständker, L.; Kirchhoff, F.; Münch, J. Exploiting the human peptidome for novel antimicrobial and anticancer agents. Bioorganic Med. Chem. 2018, 26, 2719–2726. [Google Scholar] [CrossRef] [PubMed]
  52. Pawar, S.; Markowitz, K.; Velliyagounder, K. Effect of human lactoferrin on Candida albicans infection and host response interactions in experimental oral candidiasis in mice. Arch. Oral Biol. 2022, 137, 105399. [Google Scholar] [CrossRef] [PubMed]
  53. Lupetti, A.; Brouwer, C.P.; Bogaards, S.J.; Welling, M.M.; de Heer, E.; Campa, M.; van Dissel, J.T.; Friesen, R.H.; Nibbering, P.H. Human lactoferrin-derived peptide’s antifungal activities against disseminated Candida albicans infection. J. Infect. Dis. 2007, 196, 1416–1424. [Google Scholar] [CrossRef] [PubMed]
  54. Tanida, T.; Rao, F.; Hamada, T.; Ueta, E.; Osaki, T. Lactoferrin peptide increases the survival of Candida albicans-inoculated mice by upregulating neutrophil and macrophage functions, especially in combination with amphotericin B and granulocyte-macrophage colony-stimulating factor. Infect. Immun. 2001, 69, 3883–3890. [Google Scholar] [CrossRef]
  55. Lai, Y.W.; Pang, C.N.I.; Campbell, L.T.; Chen, S.C.A.; Wilkins, M.R.; Carter, D.A. Different Pathways Mediate Amphotericin-Lactoferrin Drug Synergy in Cryptococcus and Saccharomyces. Front. Microbiol. 2019, 10, 2195. [Google Scholar] [CrossRef]
  56. Zarember, K.A.; Sugui, J.A.; Chang, Y.C.; Kwon-Chung, K.J.; Gallin, J.I. Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion. J. Immunol. 2007, 178, 6367–6373. [Google Scholar] [CrossRef]
  57. Mochon, A.B.; Liu, H. The antimicrobial peptide histatin-5 causes a spatially restricted disruption on the Candida albicans surface, allowing rapid entry of the peptide into the cytoplasm. PLoS Pathog. 2008, 4, e1000190. [Google Scholar] [CrossRef]
  58. Koshlukova, S.E.; Lloyd, T.L.; Araujo, M.W.; Edgerton, M. Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. J. Biol. Chem. 1999, 274, 18872–18879. [Google Scholar] [CrossRef]
  59. Nikawa, H.; Jin, C.; Makihira, S.; Hamada, T.; Samaranayake, L.P. Susceptibility of Candida albicans isolates from the oral cavities of HIV-positive patients to histatin-5. J. Prosthet. Dent. 2002, 88, 263–267. [Google Scholar] [CrossRef]
  60. Tsai, H.; Bobek, L.A. Human salivary histatin-5 exerts potent fungicidal activity against Cryptococcus neoformans. Biochim. Biophys. Acta 1997, 1336, 367–369. [Google Scholar] [CrossRef]
  61. Bobek, L.A.; Situ, H. MUC7 20-Mer: Investigation of antimicrobial activity, secondary structure, and possible mechanism of antifungal action. Antimicrob. Agents Chemother. 2003, 47, 643–652. [Google Scholar] [CrossRef] [PubMed]
  62. Situ, H.; Bobek, L.A. In vitro assessment of antifungal therapeutic potential of salivary histatin-5, two variants of histatin-5, and salivary mucin (MUC7) domain 1. Antimicrob. Agents Chemother. 2000, 44, 1485–1493. [Google Scholar] [CrossRef] [PubMed]
  63. Nikawa, H.; Jin, C.; Fukushima, H.; Makihira, S.; Hamada, T. Antifungal activity of histatin-5 against non-albicans Candida species. Oral Microbiol. Immunol. 2001, 16, 250–252. [Google Scholar] [CrossRef] [PubMed]
  64. van’t Hof, W.; Reijnders, I.M.; Helmerhorst, E.J.; Walgreen-Weterings, E.; Simoons-Smit, I.M.; Veerman, E.C.; Amerongen, A.V. Synergistic effects of low doses of histatin 5 and its analogues on amphotericin B anti-mycotic activity. Antonie Van Leeuwenhoek 2000, 78, 163–169. [Google Scholar] [CrossRef]
  65. Baev, D.; Li, X.S.; Dong, J.; Keng, P.; Edgerton, M. Human salivary histatin 5 causes disordered volume regulation and cell cycle arrest in Candida albicans. Infect. Immun. 2002, 70, 4777–4784. [Google Scholar] [CrossRef]
  66. Oppenheim, F.G.; Xu, T.; McMillian, F.M.; Levitz, S.M.; Diamond, R.D.; Offner, G.D.; Troxler, R.F. Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans. J. Biol. Chem. 1988, 263, 7472–7477. [Google Scholar] [CrossRef]
  67. Xu, L.; Lal, K.; Pollock, J.J. Histatins 2 and 4 are autoproteolytic degradation products of human parotid saliva. Oral Microbiol. Immunol. 1992, 7, 127–128. [Google Scholar] [CrossRef]
  68. Moulin-Traffort, J.; Venot, C.; Regli, P. Ultrastructural study of Candida albicans yeast after application of a ribonuclease. Mycopathologia 1986, 93, 121–126. [Google Scholar] [CrossRef]
  69. Sun, D.; Han, C.; Sheng, J. The role of human ribonuclease A family in health and diseases: A systematic review. iScience 2022, 25, 105284. [Google Scholar] [CrossRef]
  70. Wang, Y.N.; Lee, H.H.; Hung, M.C. A novel ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases. J. Biomed. Sci. 2018, 25, 83. [Google Scholar] [CrossRef]
  71. Rosenberg, H.F. RNase A ribonucleases and host defense: An evolving story. J. Leukoc. Biol. 2008, 83, 1079–1087. [Google Scholar] [CrossRef]
  72. Sheng, J.; Xu, Z. Three decades of research on angiogenin: A review and perspective. Acta Biochim. Biophys. Sin. 2016, 48, 399–410. [Google Scholar] [CrossRef]
  73. Zhang, J.; Dyer, K.D.; Rosenberg, H.F. Human RNase 7: A new cationic ribonuclease of the RNase A superfamily. Nucleic Acids Res. 2003, 31, 602–607. [Google Scholar] [CrossRef] [PubMed]
  74. Rademacher, F.; Simanski, M.; Harder, J. RNase 7 in Cutaneous Defense. Int. J. Mol. Sci. 2016, 17, 560. [Google Scholar] [CrossRef]
  75. Rademacher, F.; Dreyer, S.; Kopfnagel, V.; Gläser, R.; Werfel, T.; Harder, J. The Antimicrobial and Immunomodulatory Function of RNase 7 in Skin. Front. Immunol. 2019, 10, 2553. [Google Scholar] [CrossRef]
  76. Murakami, M.; Lopez-Garcia, B.; Braff, M.; Dorschner, R.A.; Gallo, R.L. Postsecretory processing generates multiple cathelicidins for enhanced topical antimicrobial defense. J. Immunol. 2004, 172, 3070–3077. [Google Scholar] [CrossRef] [PubMed]
  77. Schittek, B.; Hipfel, R.; Sauer, B.; Bauer, J.; Kalbacher, H.; Stevanovic, S.; Schirle, M.; Schroeder, K.; Blin, N.; Meier, F.; et al. Dermcidin: A novel human antibiotic peptide secreted by sweat glands. Nat. Immunol. 2001, 2, 1133–1137. [Google Scholar] [CrossRef] [PubMed]
  78. Lai, Y.; Villaruz, A.E.; Li, M.; Cha, D.J.; Sturdevant, D.E.; Otto, M. The human anionic antimicrobial peptide dermcidin induces proteolytic defence mechanisms in staphylococci. Mol. Microbiol. 2007, 63, 497–506. [Google Scholar] [CrossRef]
  79. Scarsini, M.; Tomasinsig, L.; Arzese, A.; D’Este, F.; Oro, D.; Skerlavaj, B. Antifungal activity of cathelicidin peptides against planktonic and biofilm cultures of Candida species isolated from vaginal infections. Peptides 2015, 71, 211–221. [Google Scholar] [CrossRef]
  80. van Eijk, M.; van Dijk, A.; van der Ent, C.K.; Arets, H.G.M.; Breukink, E.; van Os, N.; Adrichem, R.; van der Water, S.; Lino Gómez, R.; Kristensen, M.; et al. PepBiotics, novel cathelicidin-inspired antimicrobials to fight pulmonary bacterial infections. Biochim. Biophys. Acta. Gen. Subj. 2021, 1865, 129951. [Google Scholar] [CrossRef]
  81. Luo, X.L.; Li, J.X.; Huang, H.R.; Duan, J.L.; Dai, R.X.; Tao, R.J.; Yang, L.; Hou, J.Y.; Jia, X.M.; Xu, J.F. LL37 Inhibits Aspergillus fumigatus Infection via Directly Binding to the Fungus and Preventing Excessive Inflammation. Front. Immunol. 2019, 10, 283. [Google Scholar] [CrossRef]
  82. Biswas, D.; Ambalavanan, P.; Ravins, M.; Anand, A.; Sharma, A.; Lim, K.X.Z.; Tan, R.Y.M.; Lim, H.Y.; Sol, A.; Bachrach, G.; et al. LL-37-mediated activation of host receptors is critical for defense against group A streptococcal infection. Cell Rep. 2021, 34, 108766. [Google Scholar] [CrossRef] [PubMed]
  83. Liu, C.; Henning-Knechtel, A.; Österlund, N.; Wu, J.; Wang, G.; Gräslund, R.A.O.; Kirmizialtin, S.; Luo, J. Oligomer Dynamics of LL-37 Truncated Fragments Probed by α-Hemolysin Pore and Molecular Simulations. Small 2023, 19, e2206232. [Google Scholar] [CrossRef] [PubMed]
  84. Durnaś, B.; Wnorowska, U.; Pogoda, K.; Deptuła, P.; Wątek, M.; Piktel, E.; Głuszek, S.; Gu, X.; Savage, P.B.; Niemirowicz, K.; et al. Candidacidal Activity of Selected Ceragenins and Human Cathelicidin LL-37 in Experimental Settings Mimicking Infection Sites. PLoS ONE 2016, 11, e0157242. [Google Scholar] [CrossRef]
  85. Memariani, M.; Memariani, H. Antifungal properties of cathelicidin LL-37: Current knowledge and future research directions. World J. Microbiol. Biotechnol. 2023, 40, 34. [Google Scholar] [CrossRef] [PubMed]
  86. Hou, X.; Li, C.; Liu, J.; Yang, S.; Peng, X.; Wang, Q.; Liu, C.; Liu, X.; Luan, J.; Zhao, G.; et al. Cathelicidin boosts the antifungal activity of neutrophils and improves prognosis during Aspergillus fumigatus keratitis. Infect. Immun. 2024, 92, e0048323. [Google Scholar] [CrossRef]
  87. Sheehan, G.; Bergsson, G.; McElvaney, N.G.; Reeves, E.P.; Kavanagh, K. The Human Cathelicidin Antimicrobial Peptide LL-37 Promotes the Growth of the Pulmonary Pathogen Aspergillus fumigatus. Infect. Immun. 2018, 86, 10–1128. [Google Scholar] [CrossRef] [PubMed]
  88. Nemeth, E.; Ganz, T. Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int. J. Mol. Sci. 2021, 22, 6493. [Google Scholar] [CrossRef]
  89. Chen, R.C.; Lan, C.Y. Human Antimicrobial Peptide Hepcidin 25-Induced Apoptosis in Candida albicans. Microorganisms 2020, 8, 585. [Google Scholar] [CrossRef]
  90. Del Gaudio, G.; Lombardi, L.; Maisetta, G.; Esin, S.; Batoni, G.; Sanguinetti, M.; Senesi, S.; Tavanti, A. Antifungal Activity of the Noncytotoxic Human Peptide Hepcidin 20 against Fluconazole-Resistant Candida glabrata in Human Vaginal Fluid. Antimicrob. Agents Chemother. 2013, 57, 4314–4321. [Google Scholar] [CrossRef]
  91. Arekar, T.; Katikaneni, D.; Kasem, S.; Desai, D.; Acharya, T.; Cole, A.; Khodayari, N.; Vaulont, S.; Hube, B.; Nemeth, E.; et al. Essential role of Hepcidin in host resistance to disseminated candidiasis. biorXiv 2024. [Google Scholar] [CrossRef]
  92. Tavanti, A.; Maisetta, G.; Del Gaudio, G.; Petruzzelli, R.; Sanguinetti, M.; Batoni, G.; Senesi, S. Fungicidal activity of the human peptide hepcidin 20 alone or in combination with other antifungals against Candida glabrata isolates. Peptides 2011, 32, 2484–2487. [Google Scholar] [CrossRef] [PubMed]
  93. Lugardon, K.; Chasserot-Golaz, S.; Kieffer, A.E.; Maget-Dana, R.; Nullans, G.; Kieffer, B.; Aunis, D.; Metz-Boutigue, M.H. Structural and biological characterization of chromofungin, the antifungal chromogranin A (47-66)-derived peptide. Ann. N. Y. Acad. Sci. 2002, 971, 359–361. [Google Scholar] [CrossRef] [PubMed]
  94. Lehrer, R.I.; Lu, W. α-Defensins in human innate immunity. Immunol. Rev. 2012, 245, 84–112. [Google Scholar] [CrossRef]
  95. De Lucca, A.J.; Walsh, T.J. Antifungal peptides: Novel therapeutic compounds against emerging pathogens. Antimicrob. Agents Chemother. 1999, 43, 1–11. [Google Scholar] [CrossRef]
  96. Huang, L.; Leong, S.S.; Jiang, R. Soluble fusion expression and characterization of bioactive human beta-defensin 26 and 27. Appl. Microbiol. Biotechnol. 2009, 84, 301–308. [Google Scholar] [CrossRef]
  97. Agerberth, B.; Charo, J.; Werr, J.; Olsson, B.; Idali, F.; Lindbom, L.; Kiessling, R.; Jörnvall, H.; Wigzell, H.; Gudmundsson, G.H. The human antimicrobial and chemotactic peptides LL-37 and alpha-defensins are expressed by specific lymphocyte and monocyte populations. Blood 2000, 96, 3086–3093. [Google Scholar] [CrossRef]
  98. Vylkova, S.; Nayyar, N.; Li, W.; Edgerton, M. Human beta-defensins kill Candida albicans in an energy-dependent and salt-sensitive manner without causing membrane disruption. Antimicrob. Agents Chemother. 2007, 51, 154–161. [Google Scholar] [CrossRef]
  99. Krishnakumari, V.; Rangaraj, N.; Nagaraj, R. Antifungal activities of human beta-defensins HBD-1 to HBD-3 and their C-terminal analogs Phd1 to Phd3. Antimicrob. Agents Chemother. 2009, 53, 256–260. [Google Scholar] [CrossRef]
  100. Schneider, J.J.; Unholzer, A.; Schaller, M.; Schäfer-Korting, M.; Korting, H.C. Human defensins. J. Mol. Med. 2005, 83, 587–595. [Google Scholar] [CrossRef]
  101. Kamli, M.R.; Sabir, J.S.M.; Malik, M.A.; Ahmad, A. Human β defensins-1, an antimicrobial peptide, kills Candida glabrata by generating oxidative stress and arresting the cell cycle in G0/G1 phase. Biomed. Pharmacother. Biomed. Pharmacother. 2022, 154, 113569. [Google Scholar] [CrossRef] [PubMed]
  102. Soto, E.; Espinoza, J.; Nien, J.K.; Kusanovic, J.P.; Erez, O.; Richani, K.; Santolaya-Forgas, J.; Romero, R. Human beta-defensin-2: A natural antimicrobial peptide present in amniotic fluid participates in the host response to microbial invasion of the amniotic cavity. J. Matern. Fetal Neonatal Med. 2007, 20, 15–22. [Google Scholar] [CrossRef] [PubMed]
  103. Feng, Z.; Jiang, B.; Chandra, J.; Ghannoum, M.; Nelson, S.; Weinberg, A. Human beta-defensins: Differential activity against candidal species and regulation by Candida albicans. J. Dent. Res. 2005, 84, 445–450. [Google Scholar] [CrossRef] [PubMed]
  104. Järvå, M.; Phan, T.K.; Lay, F.T.; Caria, S.; Kvansakul, M.; Hulett, M.D. Human β-defensin 2 kills Candida albicans through phosphatidylinositol 4,5-bisphosphate-mediated membrane permeabilization. Sci. Adv. 2018, 4, eaat0979. [Google Scholar] [CrossRef]
  105. Basso, V.; Garcia, A.; Tran, D.Q.; Schaal, J.B.; Tran, P.; Ngole, D.; Aqeel, Y.; Tongaonkar, P.; Ouellette, A.J.; Selsted, M.E. Fungicidal Potency and Mechanisms of θ-Defensins against Multidrug-Resistant Candida Species. Antimicrob. Agents Chemother. 2018, 62, 10–1128. [Google Scholar] [CrossRef]
  106. Argimón, S.; Fanning, S.; Blankenship, J.R.; Mitchell, A.P. Interaction between the Candida albicans high-osmolarity glycerol (HOG) pathway and the response to human beta-defensins 2 and 3. Eukaryot. Cell 2011, 10, 272–275. [Google Scholar] [CrossRef]
  107. Dümig, M.; Binder, J.; Gaculenko, A.; Daul, F.; Winandy, L.; Hasenberg, M.; Gunzer, M.; Fischer, R.; Künzler, M.; Krappmann, S. The infectious propagules of Aspergillus fumigatus are coated with antimicrobial peptides. Cell. Microbiol. 2021, 23, e13301. [Google Scholar] [CrossRef]
  108. Alcouloumre, M.S.; Ghannoum, M.A.; Ibrahim, A.S.; Selsted, M.E.; Edwards, J.E., Jr. Fungicidal properties of defensin NP-1 and activity against Cryptococcus neoformans in vitro. Antimicrob. Agents Chemother. 1993, 37, 2628–2632. [Google Scholar] [CrossRef]
  109. Qu, X.; Wang, A. Purification and antimicrobial activity of human neutrophil defensins. Zhonghua Yi Xue Za Zhi 1991, 71, 616–619, 642. [Google Scholar]
  110. van der Weerden, N.L.; Parisi, K.; McKenna, J.A.; Hayes, B.M.; Harvey, P.J.; Quimbar, P.; Wevrett, S.R.; Veneer, P.K.; McCorkelle, O.; Vasa, S.; et al. The Plant Defensin Ppdef1 Is a Novel Topical Treatment for Onychomycosis. J. Fungi 2023, 9, 1111. [Google Scholar] [CrossRef]
  111. Vijaya Chandra, S.H.; Srinivas, R.; Dawson, T.L., Jr.; Common, J.E. Cutaneous Malassezia: Commensal, Pathogen, or Protector? Front. Cell. Infect. Microbiol. 2020, 10, 614446. [Google Scholar] [CrossRef] [PubMed]
  112. Ianiri, G.; LeibundGut-Landmann, S.; Dawson, T.L., Jr. Malassezia: A Commensal, Pathogen, and Mutualist of Human and Animal Skin. Annu. Rev. Microbiol. 2022, 76, 757–782. [Google Scholar] [CrossRef] [PubMed]
  113. Schmid, B.; Künstner, A.; Fähnrich, A.; Busch, H.; Glatz, M.; Bosshard, P.P. Longitudinal Characterization of the Fungal Skin Microbiota in Healthy Subjects Over a Period of 1 Year. J. Investig. Dermatol. 2022, 142, 2766–2772.e2768. [Google Scholar] [CrossRef] [PubMed]
  114. Leung, M.H.; Chan, K.C.; Lee, P.K. Skin fungal community and its correlation with bacterial community of urban Chinese individuals. Microbiome 2016, 4, 46. [Google Scholar] [CrossRef]
  115. Agerberth, B.; Buentke, E.; Bergman, P.; Eshaghi, H.; Gabrielsson, S.; Gudmundsson, G.H.; Scheynius, A. Malassezia sympodialis differently affects the expression of LL-37 in dendritic cells from atopic eczema patients and healthy individuals. Allergy 2006, 61, 422–430. [Google Scholar] [CrossRef]
  116. López-García, B.; Lee, P.H.; Gallo, R.L. Expression and potential function of cathelicidin antimicrobial peptides in dermatophytosis and tinea versicolor. J. Antimicrob. Chemother. 2006, 57, 877–882. [Google Scholar] [CrossRef]
  117. Khurana, A.; Sharath, S.; Sardana, K.; Chowdhary, A. Clinico-mycological and therapeutic updates on cutaneous dermatophytic infections in the era of Trichophyton indotineae. J. Am. Acad. Dermatol. 2024, 91, 315–323. [Google Scholar] [CrossRef]
  118. Cammarata, E.; Cristo, N.D.; Airoldi, C.; Veronese, F.; Esposto, E.; Giacomazzi, C.; Coppo, P.; Zavattaro, E.; Savoia, P. Trichophyton erinacei infection in humans: A case report and a literature review. J. Der Dtsch. Dermatol. Ges. 2024, 22, 1337–1342. [Google Scholar] [CrossRef] [PubMed]
  119. Leung, A.K.; Barankin, B.; Lam, J.M.; Leong, K.F.; Hon, K.L. Tinea pedis: An updated review. Drugs Context 2023, 12, 1–16. [Google Scholar] [CrossRef]
  120. Jabet, A.; Normand, A.C.; Brun, S.; Dannaoui, E.; Bachmeyer, C.; Piarroux, R.; Hennequin, C.; Moreno-Sabater, A. Trichophyton indotineae, from epidemiology to therapeutic. J. Mycol. Medicale 2023, 33, 101383. [Google Scholar] [CrossRef]
  121. Migliolo, L.; Silva, O.N.; Silva, P.A.; Costa, M.P.; Costa, C.R.; Nolasco, D.O.; Barbosa, J.A.; Silva, M.R.; Bemquerer, M.P.; Lima, L.M.; et al. Structural and functional characterization of a multifunctional alanine-rich peptide analogue from Pleuronectes americanus. PLoS ONE 2012, 7, e47047. [Google Scholar] [CrossRef] [PubMed]
  122. Lockhart, S.R.; Chowdhary, A.; Gold, J.A.W. The rapid emergence of antifungal-resistant human-pathogenic fungi. Nat. Rev. Microbiol. 2023, 21, 818–832. [Google Scholar] [CrossRef] [PubMed]
  123. Brasch, J.; Gräser, Y.; Beck-Jendroscheck, V.; Voss, K.; Torz, K.; Walther, G.; Schwarz, T. “Indian” strains of Trichophyton mentagrophytes with reduced itraconazole susceptibility in Germany. J. Der Dtsch. Dermatol. Ges. J. Ger. Soc. Dermatol. JDDG 2021, 19, 1723–1727. [Google Scholar] [CrossRef] [PubMed]
  124. Shen, J.J.; Arendrup, M.C.; Verma, S.; Saunte, D.M.L. The Emerging Terbinafine-Resistant Trichophyton Epidemic: What Is the Role of Antifungal Susceptibility Testing? Dermatology 2022, 238, 60–79. [Google Scholar] [CrossRef]
  125. Uhrlaß, S.; Verma, S.B.; Gräser, Y.; Rezaei-Matehkolaei, A.; Hatami, M.; Schaller, M.; Nenoff, P. Trichophyton indotineae—An Emerging Pathogen Causing Recalcitrant Dermatophytoses in India and Worldwide-A Multidimensional Perspective. J. Fungi 2022, 8, 757. [Google Scholar] [CrossRef]
  126. Lockhart, S.R.; Smith, D.J.; Gold, J.A.W. Trichophyton indotineae and other terbinafine-resistant dermatophytes in North America. J. Clin. Microbiol. 2023, 61, e0090323. [Google Scholar] [CrossRef]
  127. Stensen, W.; Turner, R.; Brown, M.; Kondori, N.; Svendsen, J.S.; Svenson, J. Short Cationic Antimicrobial Peptides Display Superior Antifungal Activities toward Candidiasis and Onychomycosis in Comparison with Terbinafine and Amorolfine. Mol. Pharm. 2016, 13, 3595–3600. [Google Scholar] [CrossRef]
  128. Evans, E.G. Causative pathogens in onychomycosis and the possibility of treatment resistance: A review. J. Am. Acad. Dermatol. 1998, 38, S32–S36. [Google Scholar] [CrossRef]
  129. Svenson, J.; Molchanova, N.; Schroeder, C.I. Antimicrobial Peptide Mimics for Clinical Use: Does Size Matter? Front. Immunol. 2022, 13, 915368. [Google Scholar] [CrossRef]
  130. Mercer, D.K.; Robertson, J.C.; Miller, L.; Stewart, C.S.; O’Neil, D.A. NP213 (Novexatin®): A unique therapy candidate for onychomycosis with a differentiated safety and efficacy profile. Med. Mycol. 2020, 58, 1064–1072. [Google Scholar] [CrossRef]
  131. Mercer, D.K.; Stewart, C.S.; Miller, L.; Robertson, J.; Duncan, V.M.S.; O’Neil, D.A. Improved Methods for Assessing Therapeutic Potential of Antifungal Agents against Dermatophytes and Their Application in the Development of NP213, a Novel Onychomycosis Therapy Candidate. Antimicrob. Agents Chemother. 2019, 63, 10-1128. [Google Scholar] [CrossRef] [PubMed]
  132. Nakatsuji, T.; Chen, T.H.; Narala, S.; Chun, K.A.; Two, A.M.; Yun, T.; Shafiq, F.; Kotol, P.F.; Bouslimani, A.; Melnik, A.V.; et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci. Transl. Med. 2017, 9, aah4680. [Google Scholar] [CrossRef] [PubMed]
  133. Patiño, M.I.; Restrepo, L.M.; Becerra, N.Y.; van der Mei, H.C.; van Kooten, T.G.; Sharma, P.K. Nonviral Expression of LL-37 in a Human Skin Equivalent to Prevent Infection in Skin Wounds. Hum. Gene Ther. 2021, 32, 1147–1157. [Google Scholar] [CrossRef]
  134. Kiatsurayanon, C.; Ogawa, H.; Niyonsaba, F. The Role of Host Defense Peptide Human β-defensins in the Maintenance of Skin Barriers. Curr. Pharm. Des. 2018, 24, 1092–1099. [Google Scholar] [CrossRef] [PubMed]
  135. Ryu, S.; Song, P.I.; Seo, C.H.; Cheong, H.; Park, Y. Colonization and infection of the skin by S. aureus: Immune system evasion and the response to cationic antimicrobial peptides. Int. J. Mol. Sci. 2014, 15, 8753–8772. [Google Scholar] [CrossRef]
  136. Köten, B.; Simanski, M.; Gläser, R.; Podschun, R.; Schröder, J.M.; Harder, J. RNase 7 contributes to the cutaneous defense against Enterococcus faecium. PLoS ONE 2009, 4, e6424. [Google Scholar] [CrossRef]
  137. Zeitvogel, J.; Döhner, K.; Klug, I.; Rademacher, F.; Gläser, R.; Sodeik, B.; Harder, J.; Werfel, T. The antimicrobial protein RNase 7 directly restricts herpes simplex virus infection of human keratinocytes. J. Med. Virol. 2024, 96, e29942. [Google Scholar] [CrossRef]
  138. Torrent, M.; Badia, M.; Moussaoui, M.; Sanchez, D.; Nogués, M.V.; Boix, E. Comparison of human RNase 3 and RNase 7 bactericidal action at the Gram-negative and Gram-positive bacterial cell wall. FEBS J. 2010, 277, 1713–1725. [Google Scholar] [CrossRef]
  139. Singh, S.B.; Ondeyka, J.; Harris, G.; Herath, K.; Zink, D.; Vicente, F.; Bills, G.; Collado, J.; Platas, G.; González del Val, A.; et al. Isolation, structure, and biological activity of Phaeofungin, a cyclic lipodepsipeptide from a Phaeosphaeria sp. Using the Genome-Wide Candida albicans Fitness Test. J. Nat. Prod. 2013, 76, 334–345. [Google Scholar] [CrossRef]
  140. Dahiya, R.; Gautam, H. Total synthesis and antimicrobial activity of a natural cycloheptapeptide of marine origin. Mar. Drugs 2010, 8, 2384–2394. [Google Scholar] [CrossRef]
  141. Dahiya, R.; Rampersad, S.; Ramnanansingh, T.G.; Kaur, K.; Kaur, R.; Mourya, R.; Chennupati, S.V.; Fairman, R.; Jalsa, N.K.; Sharma, A.; et al. Synthesis and Bioactivity of a Cyclopolypeptide from Caribbean Marine Sponge. Iran. J. Pharm. Res. IJPR 2020, 19, 156–170. [Google Scholar] [CrossRef] [PubMed]
  142. Fernández-Muiños, T.; Recha-Sancho, L.; López-Chicón, P.; Castells-Sala, C.; Mata, A.; Semino, C.E. Bimolecular based heparin and self-assembling hydrogel for tissue engineering applications. Acta Biomater. 2015, 16, 35–48. [Google Scholar] [CrossRef] [PubMed]
  143. Banwell, E.F.; Abelardo, E.S.; Adams, D.J.; Birchall, M.A.; Corrigan, A.; Donald, A.M.; Kirkland, M.; Serpell, L.C.; Butler, M.F.; Woolfson, D.N. Rational design and application of responsive alpha-helical peptide hydrogels. Nat. Mater. 2009, 8, 596–600. [Google Scholar] [CrossRef] [PubMed]
  144. Donati, L.; Valicenti, M.L.; Giannoni, S.; Morena, F.; Martino, S. Biomaterials Mimicking Mechanobiology: A Specific Design for a Specific Biological Application. Int. J. Mol. Sci. 2024, 25, 10386. [Google Scholar] [CrossRef]
  145. McCarty, T.P.; White, C.M.; Pappas, P.G. Candidemia and Invasive Candidiasis. Infect Dis Clin N. Am. 2021, 35, 389–413. [Google Scholar] [CrossRef] [PubMed]
  146. Kumamoto, C.A.; Gresnigt, M.S.; Hube, B. The gut, the bad and the harmless: Candida albicans as a commensal and opportunistic pathogen in the intestine. Curr. Opin. Microbiol. 2020, 56, 7–15. [Google Scholar] [CrossRef]
  147. Ibe, C.; Pohl, C.H. Epidemiology and drug resistance among Candida pathogens in Africa: Candida auris could now be leading the pack. Lancet Microbe 2024, 6, 100996. [Google Scholar] [CrossRef]
  148. Microbe, T.L. Candida auris: New clade, same challenges. Lancet Microbe 2024, 5, 100977. [Google Scholar] [CrossRef]
  149. Healthline Editorial Team. Candida fungus: Symptoms, Causes, and Treatment. Healthline. 2023. Available online: https://www.healthline.com/health/skin/candida-fungus (accessed on 1 October 2024).
  150. Trofa, D.; Gácser, A.; Nosanchuk, J.D. Candida parapsilosis, an emerging fungal pathogen. Clin. Microbiol. Rev. 2008, 21, 606–625. [Google Scholar] [CrossRef]
  151. Merck & Co., Inc. Candidiasis. MSD Manual Professional Version. 2023. Available online: https://www.msdmanuals.com/professional/infectious-diseases/fungi/candidiasis (accessed on 1 January 2025).
  152. Lewis, R.E. Overview of the changing epidemiology of candidemia. Curr. Med. Res. Opin. 2009, 25, 1732–1740. [Google Scholar] [CrossRef]
  153. Wang, Y.; Chen, H.; Xia, T.; Huang, Y. Characterization of fungal microbiota on normal ocular surface of humans. Clin. Microbiol. Infect. 2020, 26, 123.e9–123.e13. [Google Scholar] [CrossRef] [PubMed]
  154. Shivaji, S.; Jayasudha, R.; Sai Prashanthi, G.; Kalyana Chakravarthy, S.; Sharma, S. The Human Ocular Surface Fungal Microbiome. Investig. Ophthalmol. Vis. Sci. 2019, 60, 451–459. [Google Scholar] [CrossRef] [PubMed]
  155. Tuite, A.; Mullick, A.; Gros, P. Genetic analysis of innate immunity in resistance to Candida albicans. Genes Immun. 2004, 5, 576–587. [Google Scholar] [CrossRef] [PubMed]
  156. Medical News Today Editorial Team. Candidiasis and HIV: Link, Treatment, and Prevention. Medical News Today. 2023. Available online: https://www.medicalnewstoday.com/articles/candidiasis-and-hiv-link-treatment-and-prevention#prevention (accessed on 1 January 2025).
  157. Fidel, P.L., Jr. Candida-Host Interactions in HIV Disease: Implications for Oropharyngeal Candidiasis. Adv. Dent. Res. 2011, 23, 45–49. [Google Scholar] [CrossRef]
  158. van Asbeck, E.C.; Clemons, K.V.; Stevens, D.A. Candida parapsilosis: A review of its epidemiology, pathogenesis, clinical aspects, typing and antimicrobial susceptibility. Crit. Rev. Microbiol. 2009, 35, 283–309. [Google Scholar] [CrossRef]
  159. Ramos, L.S.; Fernandes, M.F.; Santos, H.L.C.; Picão, R.C.; Branquinha, M.H.; Santos, A.L.S. Candida spp. isolated from recreational coastal waters of Rio de Janeiro—Brazil: Focus on antifungal resistance and virulence attributes. Sci. Total Environ. 2024, 947, 174662. [Google Scholar] [CrossRef]
  160. Mor, A.; Nicolas, P. Isolation and structure of novel defensive peptides from frog skin. Eur. J. Biochem. 1994, 219, 145–154. [Google Scholar] [CrossRef]
  161. Dong, Z.; Hu, H.; Yu, X.; Tan, L.; Ma, C.; Xi, X.; Li, L.; Wang, L.; Zhou, M.; Chen, T.; et al. Novel Frog Skin-Derived Peptide Dermaseptin-PP for Lung Cancer Treatment: In vitro/vivo Evaluation and Anti-tumor Mechanisms Study. Front. Chem. 2020, 8, 476. [Google Scholar] [CrossRef]
  162. Hayes, B.M.; Bleackley, M.R.; Wiltshire, J.L.; Anderson, M.A.; Traven, A.; van der Weerden, N.L. Identification and mechanism of action of the plant defensin NaD1 as a new member of the antifungal drug arsenal against Candida albicans. Antimicrob. Agents Chemother. 2013, 57, 3667–3675. [Google Scholar] [CrossRef]
  163. Troeira Henriques, S.; Lawrence, N.; Chaousis, S.; Ravipati, A.S.; Cheneval, O.; Benfield, A.H.; Elliott, A.G.; Kavanagh, A.M.; Cooper, M.A.; Chan, L.Y.; et al. Redesigned Spider Peptide with Improved Antimicrobial and Anticancer Properties. ACS Chem. Biol. 2017, 12, 2324–2334. [Google Scholar] [CrossRef]
  164. Perez-Rodriguez, A.; Eraso, E.; Quindós, G.; Mateo, E. Antimicrobial Peptides with Anti-Candida Activity. Int. J. Mol. Sci. 2022, 23, 9264. [Google Scholar] [CrossRef] [PubMed]
  165. Joly, S.; Maze, C.; McCray, P.B., Jr.; Guthmiller, J.M. Human beta-defensins 2 and 3 demonstrate strain-selective activity against oral microorganisms. J. Clin. Microbiol. 2004, 42, 1024–1029. [Google Scholar] [CrossRef] [PubMed]
  166. Campese, M.; Sun, X.; Bosch, J.A.; Oppenheim, F.G.; Helmerhorst, E.J. Concentration and fate of histatins and acidic proline-rich proteins in the oral environment. Arch. Oral Biol. 2009, 54, 345–353. [Google Scholar] [CrossRef] [PubMed]
  167. Pazgier, M.; Hoover, D.M.; Yang, D.; Lu, W.; Lubkowski, J. Human beta-defensins. Cell. Mol. Life Sci. CMLS 2006, 63, 1294–1313. [Google Scholar] [CrossRef]
  168. Miura, S.; Garcet, S.; Li, X.; Cueto, I.; Salud-Gnilo, C.; Kunjravia, N.; Yamamura, K.; Gonzalez, J.; Murai-Yamamura, M.; Rambhia, D.; et al. Cathelicidin Antimicrobial Peptide LL37 Induces Toll-Like Receptor 8 and Amplifies IL-36γ and IL-17C in Human Keratinocytes. J. Investig. Dermatol. 2023, 143, 832–841.e834. [Google Scholar] [CrossRef]
  169. Inthanachai, T.; Thammahong, A.; Edwards, S.W.; Virakul, S.; Kiatsurayanon, C.; Chiewchengchol, D. The Inhibitory Effect of Human Beta-defensin-3 on Candida Glabrata Isolated from Patients with Candidiasis. Immunol. Investig. 2021, 50, 80–91. [Google Scholar] [CrossRef]
  170. Polesello, V.; Segat, L.; Crovella, S.; Zupin, L. Candida infections and human defensins. Protein Pept. Lett. 2017, 24, 747–756. [Google Scholar] [CrossRef]
  171. Sowa-Jasiłek, A.; Zdybicka-Barabas, A.; Stączek, S.; Wydrych, J.; Skrzypiec, K.; Mak, P.; Deryło, K.; Tchórzewski, M.; Cytryńska, M. Galleria mellonella lysozyme induces apoptotic changes in Candida albicans cells. Microbiol. Res. 2016, 193, 121–131. [Google Scholar] [CrossRef]
  172. Chen, Y.C.; Chen, F.J.; Lee, C.H. Effect of antifungal agents, lysozyme and human antimicrobial peptide LL-37 on clinical Candida isolates with high biofilm production. J. Med. Microbiol. 2021, 70, 001283. [Google Scholar] [CrossRef]
  173. Wu, T.; Samaranayake, L.P.; Leung, W.K.; Sullivan, P.A. Inhibition of growth and secreted aspartyl proteinase production in Candida albicans by lysozyme. J. Med. Microbiol. 1999, 48, 721–730. [Google Scholar] [CrossRef]
  174. Zolin, G.V.S.; Fonseca, F.H.D.; Zambom, C.R.; Garrido, S.S. Histatin 5 Metallopeptides and Their Potential against Candida albicans Pathogenicity and Drug Resistance. Biomolecules 2021, 11, 1209. [Google Scholar] [CrossRef] [PubMed]
  175. Veerman, E.C.; Valentijn-Benz, M.; van’t Hof, W.; Nazmi, K.; van Marle, J.; Amerongen, A.V. Phytosphingosine kills Candida albicans by disrupting its cell membrane. Biol. Chem. 2010, 391, 65–71. [Google Scholar] [CrossRef] [PubMed]
  176. Lee, J.; Lee, D.G. Melittin triggers apoptosis in Candida albicans through the reactive oxygen species-mediated mitochondria/caspase-dependent pathway. FEMS Microbiol. Lett. 2014, 355, 36–42. [Google Scholar] [CrossRef] [PubMed]
  177. Li, H.; Gong, H.; Qi, Y.; Li, J.; Ji, X.; Sun, J.; Tian, R.; Bao, H.; Song, X.; Chen, Q.; et al. In vitro and in vivo antifungal activities and mechanism of heteropolytungstates against Candida species. Sci. Rep. 2017, 7, 16942. [Google Scholar] [CrossRef]
  178. Kamai, Y.; Kakuta, M.; Shibayama, T.; Fukuoka, T.; Kuwahara, S. Antifungal activities of R-135853, a sordarin derivative, in experimental candidiasis in mice. Antimicrob. Agents Chemother. 2005, 49, 52–56. [Google Scholar] [CrossRef]
  179. Huo, X.; Li, D.; Wu, F.; Li, S.; Qiao, Y.; Wang, C.; Wang, Y.; Zhou, C.; Sun, L.; Luan, Z.; et al. Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists. Gut 2022, 71, 2205–2217. [Google Scholar] [CrossRef]
  180. Zhou, M.; Liu, L.; Cong, Z.; Jiang, W.; Xiao, X.; Xie, J.; Luo, Z.; Chen, S.; Wu, Y.; Xue, X.; et al. A dual-targeting antifungal is effective against multidrug-resistant human fungal pathogens. Nat. Microbiol. 2024, 9, 1325–1339. [Google Scholar] [CrossRef]
  181. Jung, C.J.; Liao, Y.D.; Hsu, C.C.; Huang, T.Y.; Chuang, Y.C.; Chen, J.W.; Kuo, Y.M.; Chia, J.S. Identification of potential therapeutic antimicrobial peptides against Acinetobacter baumannii in a mouse model of pneumonia. Sci. Rep. 2021, 11, 7318. [Google Scholar] [CrossRef]
  182. Bednarek, A.; Satala, D.; Zawrotniak, M.; Nobbs, A.H.; Rapala-Kozik, M.; Kozik, A. Glyceraldehyde 3-Phosphate Dehydrogenase on the Surface of Candida albicans and Nakaseomyces glabratus Cells-A Moonlighting Protein That Binds Human Vitronectin and Plasminogen and Can Adsorb to Pathogenic Fungal Cells via Major Adhesins Als3 and Epa6. Int. J. Mol. Sci. 2024, 25, 1013. [Google Scholar] [CrossRef]
  183. Pierre, J.F.; Peters, B.M.; La Torre, D.; Sidebottom, A.M.; Tao, Y.; Zhu, X.; Cham, C.M.; Wang, L.; Kambal, A.; Harris, K.G.; et al. Peptide YY: A Paneth cell antimicrobial peptide that maintains Candida gut commensalism. Science 2023, 381, 502–508. [Google Scholar] [CrossRef]
  184. Athapaththu, A.; Sanjaya, S.S.; Lee, K.T.; Karunarathne, W.; Choi, Y.H.; Hur, S.P.; Kim, G.Y. Pinostrobin Suppresses the α-Melanocyte-Stimulating Hormone-Induced Melanogenic Signaling Pathway. Int. J. Mol. Sci. 2023, 24, 821. [Google Scholar] [CrossRef] [PubMed]
  185. Böhm, M.; Schiller, M.; Luger, T.A. Non-pigmentary actions of alpha-melanocyte-stimulating hormone--lessons from the cutaneous melanocortin system. Cell. Mol. Biol. 2006, 52, 61–68. [Google Scholar] [PubMed]
  186. Rauch, I.; Holzmeister, S.; Kofler, B. Anti-Candida activity of alpha-melanocyte-stimulating hormone (alpha-MSH) peptides. J. Leukoc. Biol. 2009, 85, 371–372, author reply 373. [Google Scholar] [CrossRef] [PubMed]
  187. Luo, S.; Hoffmann, R.; Skerka, C.; Zipfel, P.F. Glycerol-3-phosphate dehydrogenase 2 is a novel factor H-, factor H-like protein 1-, and plasminogen-binding surface protein of Candida albicans. J. Infect. Dis. 2013, 207, 594–603. [Google Scholar] [CrossRef]
  188. Csato, M.; Kenderessy, A.S.; Dobozy, A. Enhancement of Candida albicans killing activity of separated human epidermal cells by alpha-melanocyte stimulating hormone. Br. J. Dermatol. 1989, 121, 145–147. [Google Scholar] [CrossRef]
  189. Grieco, P.; Rossi, C.; Colombo, G.; Gatti, S.; Novellino, E.; Lipton, J.M.; Catania, A. Novel alpha-melanocyte stimulating hormone peptide analogues with high candidacidal activity. J. Med. Chem. 2003, 46, 850–855. [Google Scholar] [CrossRef]
  190. Hein, K.Z.; Takahashi, H.; Tsumori, T.; Yasui, Y.; Nanjoh, Y.; Toga, T.; Wu, Z.; Grötzinger, J.; Jung, S.; Wehkamp, J.; et al. Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide. Proc. Natl. Acad. Sci. USA 2015, 112, 13039–13044. [Google Scholar] [CrossRef]
  191. Brauner, A.; Alvendal, C.; Chromek, M.; Stopsack, K.H.; Ehrström, S.; Schröder, J.M.; Bohm-Starke, N. Psoriasin, a novel anti-Candida albicans adhesin. J. Mol. Med. 2018, 96, 537–545. [Google Scholar] [CrossRef]
  192. Obar, J.J. Sensing the threat posed by Aspergillus infection. Curr. Opin. Microbiol. 2020, 58, 47–55. [Google Scholar] [CrossRef]
  193. Cadena, J.; Thompson, G.R., 3rd; Patterson, T.F. Aspergillosis: Epidemiology, Diagnosis, and Treatment. Infect. Dis. Clin. N. Am. 2021, 35, 415–434. [Google Scholar] [CrossRef]
  194. Zahid, A.; Waqas, S. Importance of excluding invasive aspergillus infection prior to immunosuppression. J. R. Coll. Physicians Edinb. 2022, 52, 184. [Google Scholar] [CrossRef] [PubMed]
  195. Rieber, N.; Gazendam, R.P.; Freeman, A.F.; Hsu, A.P.; Collar, A.L.; Sugui, J.A.; Drummond, R.A.; Rongkavilit, C.; Hoffman, K.; Henderson, C.; et al. Extrapulmonary Aspergillus infection in patients with CARD9 deficiency. JCI Insight 2016, 1, e89890. [Google Scholar] [CrossRef] [PubMed]
  196. Dimopoulos, G.; Almyroudi, M.P.; Myrianthefs, P.; Rello, J. COVID-19-Associated Pulmonary Aspergillosis (CAPA). J. Intensive Med. 2021, 1, 71–80. [Google Scholar] [CrossRef] [PubMed]
  197. Machado, M.; Fortún, J.; Muñoz, P. Invasive aspergillosis: A comprehensive review. Med. Clin. 2024, 163, 189–198. [Google Scholar] [CrossRef]
  198. Amaike, S.; Keller, N.P. Aspergillus flavus. Annu. Rev. Phytopathol. 2011, 49, 107–133. [Google Scholar] [CrossRef]
  199. Krishnan, S.; Manavathu, E.K.; Chandrasekar, P.H. Aspergillus flavus: An emerging non-fumigatus Aspergillus species of significance. Mycoses 2009, 52, 206–222. [Google Scholar] [CrossRef]
  200. Cairns, T.C.; Barthel, L.; Meyer, V. Something old, something new: Challenges and developments in Aspergillus niger biotechnology. Essays Biochem. 2021, 65, 213–224. [Google Scholar] [CrossRef]
  201. Nielsen, K.F.; Mogensen, J.M.; Johansen, M.; Larsen, T.O.; Frisvad, J.C. Review of secondary metabolites and mycotoxins from the Aspergillus niger group. Anal. Bioanal. Chem. 2009, 395, 1225–1242. [Google Scholar] [CrossRef]
  202. Ballard, E.; Yucel, R.; Melchers, W.J.G.; Brown, A.J.P.; Verweij, P.E.; Warris, A. Antifungal Activity of Antimicrobial Peptides and Proteins against Aspergillus fumigatus. J. Fungi 2020, 6, 65. [Google Scholar] [CrossRef]
  203. Oguiura, N.; Corrêa, P.G.; Rosmino, I.L.; de Souza, A.O.; Pasqualoto, K.F.M. Antimicrobial Activity of Snake β-Defensins and Derived Peptides. Toxins 2021, 14, 1. [Google Scholar] [CrossRef]
  204. Alekseeva, L.; Huet, D.; Féménia, F.; Mouyna, I.; Abdelouahab, M.; Cagna, A.; Guerrier, D.; Tichanné-Seltzer, V.; Baeza-Squiban, A.; Chermette, R.; et al. Inducible expression of beta defensins by human respiratory epithelial cells exposed to Aspergillus fumigatus organisms. BMC Microbiol. 2009, 9, 33. [Google Scholar] [CrossRef] [PubMed]
  205. Corrêa-Almeida, C.; Borba-Santos, L.P.; Rollin-Pinheiro, R.; Barreto-Bergter, E.; Rozental, S.; Kurtenbach, E. Characterization of Aspergillus nidulans Biofilm Formation and Structure and Their Inhibition by Pea Defensin Psd2. Front. Mol. Biosci. 2022, 9, 795255. [Google Scholar] [CrossRef] [PubMed]
  206. Mambula, S.S.; Simons, E.R.; Hastey, R.; Selsted, M.E.; Levitz, S.M. Human neutrophil-mediated nonoxidative antifungal activity against Cryptococcus neoformans. Infect. Immun. 2000, 68, 6257–6264. [Google Scholar] [CrossRef]
  207. Datta, A.; Yadav, V.; Ghosh, A.; Choi, J.; Bhattacharyya, D.; Kar, R.K.; Ilyas, H.; Dutta, A.; An, E.; Mukhopadhyay, J.; et al. Mode of Action of a Designed Antimicrobial Peptide: High Potency against Cryptococcus neoformans. Biophys. J. 2016, 111, 1724–1737. [Google Scholar] [CrossRef] [PubMed]
  208. Zhao, Y.; Ye, L.; Zhao, F.; Zhang, L.; Lu, Z.; Chu, T.; Wang, S.; Liu, Z.; Sun, Y.; Chen, M.; et al. Cryptococcus neoformans, a global threat to human health. Infect. Dis. Poverty 2023, 12, 20. [Google Scholar] [CrossRef]
  209. Conti, S.; Radicioni, G.; Ciociola, T.; Longhi, R.; Polonelli, L.; Gatti, R.; Cabras, T.; Messana, I.; Castagnola, M.; Vitali, A. Structural and functional studies on a proline-rich peptide isolated from swine saliva endowed with antifungal activity towards Cryptococcus neoformans. Biochim. Biophys. Acta 2013, 1828, 1066–1074. [Google Scholar] [CrossRef]
  210. Xue, A.; Robbins, N.; Cowen, L.E. Advances in fungal chemical genomics for the discovery of new antifungal agents. Ann. N. Y. Acad. Sci. 2021, 1496, 5–22. [Google Scholar] [CrossRef]
  211. Deng, H.; Song, J.; Huang, Y.; Yang, C.; Zang, X.; Zhou, Y.; Li, H.; Dai, B.; Xue, X. Combating increased antifungal drug resistance in Cryptococcus, what should we do in the future? Acta Biochim. Biophys. Sin. 2023, 55, 540–547. [Google Scholar] [CrossRef]
  212. Iyer, K.R.; Revie, N.M.; Fu, C.; Robbins, N.; Cowen, L.E. Treatment strategies for cryptococcal infection: Challenges, advances and future outlook. Nat. Rev. Microbiol. 2021, 19, 454–466. [Google Scholar] [CrossRef]
  213. Su, Y.; Zhao, L.; Meng, F.; Wang, Q.; Yao, Y.; Luo, J. Silver nanoparticles decorated lipase-sensitive polyurethane micelles for on-demand release of silver nanoparticles. Colloids Surf. B Biointerfaces 2017, 152, 238–244. [Google Scholar] [CrossRef]
  214. Wang, H.; Xu, K.; Liu, L.; Tan, J.P.K.; Chen, Y.; Li, Y.; Fan, W.; Wei, Z.; Sheng, J.; Yang, Y.-Y.; et al. The efficacy of self-assembled cationic antimicrobial peptide nanoparticles against Cryptococcus neoformans for the treatment of meningitis. Biomaterials 2010, 31, 2874–2881. [Google Scholar] [CrossRef] [PubMed]
  215. Araúz, A.B.; Papineni, P. Histoplasmosis. Infect. Dis. Clin. North Am. 2021, 35, 471–491. [Google Scholar] [CrossRef] [PubMed]
  216. Barros, N.; Wheat, J.L.; Hage, C. Pulmonary Histoplasmosis: A Clinical Update. J. Fungi 2023, 9, 236. [Google Scholar] [CrossRef] [PubMed]
  217. Gugnani, H.C.; Denning, D.W. Infection of bats with Histoplasma species. Med. Mycol. 2023, 61, myad080. [Google Scholar] [CrossRef]
  218. Couto, M.A.; Liu, L.; Lehrer, R.I.; Ganz, T. Inhibition of intracellular Histoplasma capsulatum replication by murine macrophages that produce human defensin. Infect. Immun. 1994, 62, 2375–2378. [Google Scholar] [CrossRef]
  219. Gomez, F.J.; Allendoerfer, R.; Deepe, G.S., Jr. Vaccination with recombinant heat shock protein 60 from Histoplasma capsulatum protects mice against pulmonary histoplasmosis. Infect. Immun. 1995, 63, 2587–2595. [Google Scholar] [CrossRef]
  220. Milewski, S.; Mignini, F.; Micossi, L.; Borowski, E. Antihistoplasmal in vitro and in vivo effect of Lys-Nva-FMDP. Med. Mycol. 1998, 36, 177–180. [Google Scholar] [CrossRef]
  221. Milewski, S.; Andruszkiewicz, R.; Kasprzak, L.; Mazerski, J.; Mignini, F.; Borowski, E. Mechanism of action of anticandidal dipeptides containing inhibitors of glucosamine-6-phosphate synthase. Antimicrob. Agents Chemother. 1991, 35, 36–43. [Google Scholar] [CrossRef]
  222. de la Salud Bea, R.; North, L.J.; Horiuchi, S.; Frawley, E.R.; Shen, Q. Antimicrobial Activity and Toxicity of Analogs of Wasp Venom EMP Peptides. Potential Influence of Oxidized Methionine. Antibiotics 2021, 10, 1208. [Google Scholar] [CrossRef]
  223. Xie, L.; Fang, W.; Deng, W.; Yu, Z.; Li, J.; Chen, M.; Liao, W.; Xie, J.; Pan, W. Global profiling of lysine acetylation in human histoplasmosis pathogen Histoplasma capsulatum. Int. J. Biochem. Cell Biol. 2016, 73, 1–10. [Google Scholar] [CrossRef]
  224. Woo, P.C.; Tam, E.W.; Chong, K.T.; Cai, J.J.; Tung, E.T.; Ngan, A.H.; Lau, S.K.; Yuen, K.Y. High diversity of polyketide synthase genes and the melanin biosynthesis gene cluster in Penicillium marneffei. FEBS J. 2010, 277, 3750–3758. [Google Scholar] [CrossRef] [PubMed]
  225. de Oliveira, H.C.; Assato, P.A.; Marcos, C.M.; Scorzoni, L.; de Paula, E.S.A.C.; Da Silva Jde, F.; Singulani Jde, L.; Alarcon, K.M.; Fusco-Almeida, A.M.; Mendes-Giannini, M.J. Paracoccidioides-host Interaction: An Overview on Recent Advances in the Paracoccidioidomycosis. Front. Microbiol. 2015, 6, 1319. [Google Scholar] [CrossRef] [PubMed]
  226. Pappagianis, D.; Zimmer, B.L. Serology of coccidioidomycosis. Clin. Microbiol. Rev. 1990, 3, 247–268. [Google Scholar] [CrossRef] [PubMed]
  227. Saubolle, M.A. Laboratory aspects in the diagnosis of coccidioidomycosis. Ann. N. Y. Acad. Sci. 2007, 1111, 301–314. [Google Scholar] [CrossRef]
  228. Duarte-Escalante, E.; Frías-De-León, M.G.; Zúñiga, G.; Martínez-Herrera, E.; Acosta-Altamirano, G.; Reyes-Montes Mdel, R. Molecular markers in the epidemiology and diagnosis of coccidioidomycosis. Rev. Iberoam. Micol. 2014, 31, 49–53. [Google Scholar] [CrossRef]
  229. Barker, B.M.; Jewell, K.A.; Kroken, S.; Orbach, M.J. The population biology of coccidioides: Epidemiologic implications for disease outbreaks. Ann. N. Y. Acad. Sci. 2007, 1111, 147–163. [Google Scholar] [CrossRef]
  230. Klein, B.S.; Sondel, P.M.; Jones, J.M. WI-1, a novel 120-kilodalton surface protein on Blastomyces dermatitidis yeast cells, is a target antigen of cell-mediated immunity in human blastomycosis. Infect. Immun. 1992, 60, 4291–4300. [Google Scholar] [CrossRef]
  231. Klein, B.S.; Jones, J.M. Purification and characterization of the major antigen WI-1 from Blastomyces dermatitidis yeasts and immunological comparison with A antigen. Infect. Immun. 1994, 62, 3890–3900. [Google Scholar] [CrossRef]
  232. Cox, R.A.; Dolan, M.J.; Magee, D.M.; Galgiani, J.N. Production of a murine monoclonal antibody that recognizes an epitope specific to Coccidioides immitis antigen 2. Infect. Immun. 1993, 61, 1895–1899. [Google Scholar] [CrossRef]
  233. Steinbrink, J.M.; Miceli, M.H. Mucormycosis. Infect. Dis. Clin. N. Am. 2021, 35, 435–452. [Google Scholar] [CrossRef]
  234. Lanternier, F.; Sun, H.Y.; Ribaud, P.; Singh, N.; Kontoyiannis, D.P.; Lortholary, O. Mucormycosis in organ and stem cell transplant recipients. Clin. Infect. Dis. 2012, 54, 1629–1636. [Google Scholar] [CrossRef] [PubMed]
  235. Robin, C.; Alanio, A.; Cordonnier, C. Mucormycosis: A new concern in the transplant ward? Curr. Opin. Hematol. 2014, 21, 482–490. [Google Scholar] [CrossRef] [PubMed]
  236. Papon, N.; Naglik, J.R.; Hube, B.; Goldman, G.H. Fungal pathogenesis: A new venom. Curr. Biol. CB 2021, 31, R391–R394. [Google Scholar] [CrossRef]
  237. Giger, G.H.; Ernst, C.; Richter, I.; Gassler, T.; Field, C.M.; Sintsova, A.; Kiefer, P.; Gäbelein, C.G.; Guillaume-Gentil, O.; Scherlach, K.; et al. Inducing novel endosymbioses by implanting bacteria in fungi. Nature 2024, 635, 415–422. [Google Scholar] [CrossRef] [PubMed]
  238. Sharma, A.; Alam, M.A.; Dhoundiyal, S.; Sharma, P.K. Review on Mucormycosis: Pathogenesis, Epidemiology, Microbiology and Diagnosis. Infect. Disord. Drug Targets 2024, 24, e220823220209. [Google Scholar] [CrossRef]
  239. Gomes, M.Z.; Lewis, R.E.; Kontoyiannis, D.P. Mucormycosis caused by unusual mucormycetes, non-Rhizopus, -Mucor, and -Lichtheimia species. Clin. Microbiol. Rev. 2011, 24, 411–445. [Google Scholar] [CrossRef]
  240. Chowdhary, A.; Kathuria, S.; Singh, P.K.; Sharma, B.; Dolatabadi, S.; Hagen, F.; Meis, J.F. Molecular characterization and in vitro antifungal susceptibility of 80 clinical isolates of mucormycetes in Delhi, India. Mycoses 2014, 57 (Suppl. S3), 97–107. [Google Scholar] [CrossRef]
  241. Walther, G.; Wagner, L.; Kurzai, O. Updates on the Taxonomy of Mucorales with an Emphasis on Clinically Important Taxa. J. Fungi 2019, 5, 106. [Google Scholar] [CrossRef]
  242. Roden, M.M.; Zaoutis, T.E.; Buchanan, W.L.; Knudsen, T.A.; Sarkisova, T.A.; Schaufele, R.L.; Sein, M.; Sein, T.; Chiou, C.C.; Chu, J.H.; et al. Epidemiology and outcome of zygomycosis: A review of 929 reported cases. Clin. Infect. Dis. 2005, 41, 634–653. [Google Scholar] [CrossRef]
  243. Vaezi, A.; Moazeni, M.; Rahimi, M.T.; de Hoog, S.; Badali, H. Mucormycosis in Iran: A systematic review. Mycoses 2016, 59, 402–415. [Google Scholar] [CrossRef]
  244. Bakhshaee, M.; Bojdi, A.; Allahyari, A.; Majidi, M.R.; Tavakol, S.; Najafzadeh, M.J.; Asghari, M. Acute invasive fungal rhinosinusitis: Our experience with 18 cases. Eur. Arch. Oto-Rhino-Laryngol. 2016, 273, 4281–4287. [Google Scholar] [CrossRef] [PubMed]
  245. Shen, M.; Wang, J.; Lei, M.; Wang, Z. The outcome and the risk factors of mucormycosis among patients with hematological diseases: A systematic and meta-analysis. Front. Med. 2023, 10, 1268840. [Google Scholar] [CrossRef] [PubMed]
  246. Lax, C.; Cánovas-Márquez, J.T.; Tahiri, G.; Navarro, E.; Garre, V.; Nicolás, F.E. Genetic Manipulation in Mucorales and New Developments to Study Mucormycosis. Int. J. Mol. Sci. 2022, 23, 3454. [Google Scholar] [CrossRef] [PubMed]
  247. Lax, C.; Nicolás, F.E.; Navarro, E.; Garre, V. Molecular mechanisms that govern infection and antifungal resistance in Mucorales. Microbiol. Mol. Biol. Rev. MMBR 2024, 88, e0018822. [Google Scholar] [CrossRef]
  248. Lax, C.; Mondo, S.J.; Osorio-Concepción, M.; Muszewska, A.; Corrochano-Luque, M.; Gutiérrez, G.; Riley, R.; Lipzen, A.; Guo, J.; Hundley, H.; et al. Symmetric and asymmetric DNA N6-adenine methylation regulates different biological responses in Mucorales. Nat. Commun. 2024, 15, 6066. [Google Scholar] [CrossRef]
  249. Szebenyi, C.; Gu, Y.; Gebremariam, T.; Kocsubé, S.; Kiss-Vetráb, S.; Jáger, O.; Patai, R.; Spisák, K.; Sinka, R.; Binder, U.; et al. cotH Genes Are Necessary for Normal Spore Formation and Virulence in Mucor lusitanicus. mBio 2023, 14, e0338622. [Google Scholar] [CrossRef]
  250. Tahiri, G.; Lax, C.; Cánovas-Márquez, J.T.; Carrillo-Marín, P.; Sanchis, M.; Navarro, E.; Garre, V.; Nicolás, F.E. Mucorales and Mucormycosis: Recent Insights and Future Prospects. J. Fungi 2023, 9, 335. [Google Scholar] [CrossRef]
  251. Soare, A.Y.; Bruno, V.M. Mucorales fungi suppress nitric oxide production by macrophages. mBio 2024, 15, e0284823. [Google Scholar] [CrossRef]
  252. Liang, G.; Zhang, M.; Xu, W.; Wang, X.; Zheng, H.; Mei, H.; Liu, W. Characterization of mitogenomes from four Mucorales species and insights into pathogenicity. Mycoses 2022, 65, 45–56. [Google Scholar] [CrossRef]
  253. Liang, M.; Xu, J.; Luo, Y.; Qu, J. Epidemiology, pathogenesis, clinical characteristics, and treatment of mucormycosis: A review. Ann. Med. 2024, 56, 2396570. [Google Scholar] [CrossRef]
  254. Alqarihi, A.; Kontoyiannis, D.P.; Ibrahim, A.S. Mucormycosis in 2023: An update on pathogenesis and management. Front. Cell Infect. Microbiol. 2023, 13, 1254919. [Google Scholar] [CrossRef] [PubMed]
  255. Lugito, N.P.H.; Cucunawangsih, C. How Does Mucorales Benefit from the Dysregulated Iron Homeostasis During SARS-CoV-2 Infection? Mycopathologia 2021, 186, 877–882. [Google Scholar] [CrossRef] [PubMed]
  256. Ghosh, A.K.; Singh, R.; Reddy, S.; Singh, S.; Rudramurthy, S.M.; Kaur, H.; Choudhary, H.; Chakrabarti, A. Evaluation of environmental Mucorales contamination in and around the residence of COVID-19-associated mucormycosis patients. Front. Cell. Infect. Microbiol. 2022, 12, 953750. [Google Scholar] [CrossRef] [PubMed]
  257. Ahammed, K.S.; van Hoof, A. Fungi of the order Mucorales express a “sealing-only” tRNA ligase. RNA 2024, 30, 354–366. [Google Scholar] [CrossRef]
  258. Pinder, C.; Lebedinec, R.; Levine, T.P.; Birch, M.; Oliver, J.D. Characterisation of putative class 1A DHODH-like proteins from Mucorales and dematiaceous mould species. PLoS ONE 2023, 18, e0289441. [Google Scholar] [CrossRef]
  259. Suguna, K.; Padlan, E.A.; Smith, C.W.; Carlson, W.D.; Davies, D.R. Binding of a reduced peptide inhibitor to the aspartic proteinase from Rhizopus chinensis: Implications for a mechanism of action. Proc. Natl. Acad. Sci. USA 1987, 84, 7009–7013. [Google Scholar] [CrossRef]
  260. Gebremariam, T.; Alkhazraji, S.; Soliman, S.S.M.; Gu, Y.; Jeon, H.H.; Zhang, L.; French, S.W.; Stevens, D.A.; Edwards, J.E., Jr.; Filler, S.G.; et al. Anti-CotH3 antibodies protect mice from mucormycosis by prevention of invasion and augmenting opsonophagocytosis. Sci. Adv. 2019, 5, eaaw1327. [Google Scholar] [CrossRef]
  261. Badosa, E.; Ferré, R.; Francés, J.; Bardají, E.; Feliu, L.; Planas, M.; Montesinos, E. Sporicidal activity of synthetic antifungal undecapeptides and control of Penicillium rot of apples. Appl. Environ. Microbiol. 2009, 75, 5563–5569. [Google Scholar] [CrossRef]
  262. Liu, S.H.; Chou, W.I.; Sheu, C.C.; Chang, M.D. Improved secretory production of glucoamylase in Pichia pastoris by combination of genetic manipulations. Biochem. Biophys. Res. Commun. 2005, 326, 817–824. [Google Scholar] [CrossRef]
  263. López-García, B.; Veyrat, A.; Pérez-Payá, E.; González-Candelas, L.; Marcos, J.F. Comparison of the activity of antifungal hexapeptides and the fungicides thiabendazole and imazalil against postharvest fungal pathogens. Int. J. Food Microbiol. 2003, 89, 163–170. [Google Scholar] [CrossRef]
  264. Wang, F.; Han, R.; Chen, S. An Overlooked and Underrated Endemic Mycosis-Talaromycosis and the Pathogenic Fungus Talaromyces marneffei. Clin. Microbiol. Rev. 2023, 36, e0005122. [Google Scholar] [CrossRef] [PubMed]
  265. Yang, S.; Lou, L.; Ma, S.; Wang, H.; Rong, L.; Liu, Y.; Zhang, K.; Ai, Q.; Shi, X. Disseminated Talaromyces marneffei infection initially presenting as cutaneous and subcutaneous lesion in an HIV-Negative renal transplant recipient: A case report and literature review. BMC Infect. Dis. 2024, 24, 473. [Google Scholar] [CrossRef] [PubMed]
  266. Chan, J.F.; Lau, S.K.; Yuen, K.Y.; Woo, P.C. Talaromyces (Penicillium) marneffei infection in non-HIV-infected patients. Emerg. Microbes Infect. 2016, 5, e19. [Google Scholar] [CrossRef] [PubMed]
  267. Wong, S.S.Y.; Siau, H.; Yuen, K.Y. Penicilliosis marneffei—West meets East. J. Med. Microbiol. 1999, 48, 973–975. [Google Scholar] [CrossRef]
  268. Vanittanakom, N.; Cooper, C.R., Jr.; Fisher, M.C.; Sirisanthana, T. Penicillium marneffei infection and recent advances in the epidemiology and molecular biology aspects. Clin. Microbiol. Rev. 2006, 19, 95–110. [Google Scholar] [CrossRef]
  269. Xu, L.; Chen, X.; Yang, X.; Jiang, H.; Wang, J.; Chen, S.; Xu, J. Disseminated Talaromyces marneffei infection after renal transplantation: A case report and literature review. Front. Cell. Infect. Microbiol. 2023, 13, 1115268. [Google Scholar] [CrossRef]
  270. You, C.Y.; Hu, F.; Lu, S.W.; Pi, D.D.; Xu, F.; Liu, C.J.; Fu, Y.Q. Talaromyces Marneffei Infection in an HIV-Negative Child with a CARD9 Mutation in China: A Case Report and Review of the Literature. Mycopathologia 2021, 186, 553–561. [Google Scholar] [CrossRef]
  271. Ustianowski, A.P.; Sieu, T.P.; Day, J.N. Penicillium marneffei infection in HIV. Curr. Opin. Infect. Dis. 2008, 21, 31–36. [Google Scholar] [CrossRef]
  272. Lam, W.H.; Sze, K.H.; Ke, Y.; Tse, M.K.; Zhang, H.; Woo, P.C.Y.; Lau, S.K.P.; Lau, C.C.Y.; Xu, S.; Lai, P.M.; et al. Talaromyces marneffei Mp1 Protein, a Novel Virulence Factor, Carries Two Arachidonic Acid-Binding Domains To Suppress Inflammatory Responses in Hosts. Infect. Immun. 2019, 87, 10–1128. [Google Scholar] [CrossRef]
  273. Cao, L.; Chan, C.M.; Lee, C.; Wong, S.S.; Yuen, K.Y. MP1 encodes an abundant and highly antigenic cell wall mannoprotein in the pathogenic fungus Penicillium marneffei. Infect. Immun. 1998, 66, 966–973. [Google Scholar] [CrossRef]
  274. Erdem Büyükkiraz, M.; Kesmen, Z. Antimicrobial peptides (AMPs): A promising class of antimicrobial compounds. J. Appl. Microbiol. 2022, 132, 1573–1596. [Google Scholar] [CrossRef] [PubMed]
  275. Zhu, Y.; Hao, W.; Wang, X.; Ouyang, J.; Deng, X.; Yu, H.; Wang, Y. Antimicrobial peptides, conventional antibiotics, and their synergistic utility for the treatment of drug-resistant infections. Med. Res. Rev. 2022, 42, 1377–1422. [Google Scholar] [CrossRef] [PubMed]
  276. Morrison, L.; Zembower, T.R. Antimicrobial Resistance. Gastrointest. Endosc. Clin. N. Am. 2020, 30, 619–635. [Google Scholar] [CrossRef] [PubMed]
  277. Brinkac, L.; Voorhies, A.; Gomez, A.; Nelson, K.E. The Threat of Antimicrobial Resistance on the Human Microbiome. Microb. Ecol. 2017, 74, 1001–1008. [Google Scholar] [CrossRef]
  278. Ji, S.; An, F.; Zhang, T.; Lou, M.; Guo, J.; Liu, K.; Zhu, Y.; Wu, J.; Wu, R. Antimicrobial peptides: An alternative to traditional antibiotics. Eur. J. Med. Chem. 2024, 265, 116072. [Google Scholar] [CrossRef]
  279. Schroeder, B.O.; Wu, Z.; Nuding, S.; Groscurth, S.; Marcinowski, M.; Beisner, J.; Buchner, J.; Schaller, M.; Stange, E.F.; Wehkamp, J. Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1. Nature 2011, 469, 419–423. [Google Scholar] [CrossRef]
  280. Sharma, D.; Bisht, G.S. Recent Updates on Antifungal Peptides. Mini Rev. Med. Chem. 2020, 20, 260–268. [Google Scholar] [CrossRef]
  281. Luo, Y.; Song, Y. Mechanism of Antimicrobial Peptides: Antimicrobial, Anti-Inflammatory and Antibiofilm Activities. Int. J. Mol. Sci. 2021, 22, 11401. [Google Scholar] [CrossRef]
  282. Sani, M.A.; Separovic, F. How Membrane-Active Peptides Get into Lipid Membranes. Acc. Chem. Res. 2016, 49, 1130–1138. [Google Scholar] [CrossRef]
  283. Fabisiak, A.; Murawska, N.; Fichna, J. LL-37: Cathelicidin-related antimicrobial peptide with pleiotropic activity. Pharmacol. Rep. PR 2016, 68, 802–808. [Google Scholar] [CrossRef]
  284. Hein, M.J.A.; Kvansakul, M.; Lay, F.T.; Phan, T.K.; Hulett, M.D. Defensin-lipid interactions in membrane targeting: Mechanisms of action and opportunities for the development of antimicrobial and anticancer therapeutics. Biochem. Soc. Trans. 2022, 50, 423–437. [Google Scholar] [CrossRef] [PubMed]
  285. Gbala, I.D.; Macharia, R.W.; Bargul, J.L.; Magoma, G. Membrane Permeabilization and Antimicrobial Activity of Recombinant Defensin-d2 and Actifensin against Multidrug-Resistant Pseudomonas aeruginosa and Candida albicans. Molecules 2022, 27, 4325. [Google Scholar] [CrossRef] [PubMed]
  286. Brogden, K.A. Antimicrobial peptides: Pore formers or metabolic inhibitors in bacteria? Nat. Rev. Microbiol. 2005, 3, 238–250. [Google Scholar] [CrossRef] [PubMed]
  287. Matsuzaki, K. Membrane Permeabilization Mechanisms. Adv. Exp. Med. Biol. 2019, 1117, 9–16. [Google Scholar] [CrossRef]
  288. Jacob, T.; Kahn, T.W. A deep learning model to detect novel pore-forming proteins. Sci. Rep. 2022, 12, 2013. [Google Scholar] [CrossRef]
  289. Henriksen, J.R.; Andresen, T.L.; Feldborg, L.N.; Duelund, L.; Ipsen, J.H. Understanding detergent effects on lipid membranes: A model study of lysolipids. Biophys. J. 2010, 98, 2199–2205. [Google Scholar] [CrossRef]
  290. Nagaoka, I.; Tamura, H.; Reich, J. Therapeutic Potential of Cathelicidin Peptide LL-37, an Antimicrobial Agent, in a Murine Sepsis Model. Int. J. Mol. Sci. 2020, 21, 5973. [Google Scholar] [CrossRef]
  291. Ordonez, S.R.; Amarullah, I.H.; Wubbolts, R.W.; Veldhuizen, E.J.; Haagsman, H.P. Fungicidal mechanisms of cathelicidins LL-37 and CATH-2 revealed by live-cell imaging. Antimicrob. Agents Chemother. 2014, 58, 2240–2248. [Google Scholar] [CrossRef]
  292. den Hertog, A.L.; van Marle, J.; van Veen, H.A.; Van’t Hof, W.; Bolscher, J.G.; Veerman, E.C.; Nieuw Amerongen, A.V. Candidacidal effects of two antimicrobial peptides: Histatin 5 causes small membrane defects, but LL-37 causes massive disruption of the cell membrane. Biochem. J. 2005, 388, 689–695. [Google Scholar] [CrossRef]
  293. Rather, I.A.; Sabir, J.S.M.; Asseri, A.H.; Ali, S. Antifungal Activity of Human Cathelicidin LL-37, a Membrane Disrupting Peptide, by Triggering Oxidative Stress and Cell Cycle Arrest in Candida auris. J. Fungi 2022, 8, 204. [Google Scholar] [CrossRef]
  294. Hsu, C.M.; Liao, Y.L.; Chang, C.K.; Lan, C.Y. Candida albicans Sfp1 Is Involved in the Cell Wall and Endoplasmic Reticulum Stress Responses Induced by Human Antimicrobial Peptide LL-37. Int. J. Mol. Sci. 2021, 22, 10633. [Google Scholar] [CrossRef] [PubMed]
  295. Wang, D.; Shi, J.; Chen, C.; Wang, Z.; Liu, Y. Truncated Pleurocidin Derivative with High Pepsin Hydrolysis Resistance to Combat Multidrug-Resistant Pathogens. Pharmaceutics 2022, 14, 2025. [Google Scholar] [CrossRef] [PubMed]
  296. Mhlongo, J.T.; Waddad, A.Y.; Albericio, F.; de la Torre, B.G. Antimicrobial Peptide Synergies for Fighting Infectious Diseases. Adv. Sci. 2023, 10, e2300472. [Google Scholar] [CrossRef] [PubMed]
  297. Pushpanathan, M.; Gunasekaran, P.; Rajendhran, J. Antimicrobial peptides: Versatile biological properties. Int. J. Pept. 2013, 2013, 675391. [Google Scholar] [CrossRef]
  298. Wang, H.; Zhang, C.; Li, M.; Liu, C.; Wang, J.; Ou, X.; Han, Y. Antimicrobial Peptides Mediate Apoptosis by Changing Mitochondrial Membrane Permeability. Int. J. Mol. Sci. 2022, 23, 12732. [Google Scholar] [CrossRef]
  299. Serezani, C.H.; Ballinger, M.N.; Aronoff, D.M.; Peters-Golden, M. Cyclic AMP: Master regulator of innate immune cell function. Am. J. Respir. Cell Mol. Biol. 2008, 39, 127–132. [Google Scholar] [CrossRef]
  300. Yang, K.; Han, W.; Jiang, X.; Piffko, A.; Bugno, J.; Han, C.; Li, S.; Liang, H.; Xu, Z.; Zheng, W.; et al. Zinc cyclic di-AMP nanoparticles target and suppress tumours via endothelial STING activation and tumour-associated macrophage reinvigoration. Nat. Nanotechnol. 2022, 17, 1322–1331. [Google Scholar] [CrossRef]
  301. Akdis, C.A.; Arkwright, P.D.; Brüggen, M.C.; Busse, W.; Gadina, M.; Guttman-Yassky, E.; Kabashima, K.; Mitamura, Y.; Vian, L.; Wu, J.; et al. Type 2 immunity in the skin and lungs. Allergy 2020, 75, 1582–1605. [Google Scholar] [CrossRef]
  302. Lee, S.M.; Son, K.N.; Shah, D.; Ali, M.; Balasubramaniam, A.; Shukla, D.; Aakalu, V.K. Histatin-1 Attenuates LPS-Induced Inflammatory Signaling in RAW264.7 Macrophages. Int. J. Mol. Sci. 2021, 22, 7856. [Google Scholar] [CrossRef]
  303. Minns, D.; Smith, K.J.; Alessandrini, V.; Hardisty, G.; Melrose, L.; Jackson-Jones, L.; MacDonald, A.S.; Davidson, D.J.; Gwyer Findlay, E. The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation. Nat. Commun. 2021, 12, 1285. [Google Scholar] [CrossRef]
  304. Ren, H.; Zhao, F.; Zhang, Q.; Huang, X.; Wang, Z. Autophagy and skin wound healing. Burn. Trauma 2022, 10, tkac003. [Google Scholar] [CrossRef] [PubMed]
  305. Yang, Y.; Zhang, J.; Wu, S.; Deng, Y.; Wang, S.; Xie, L.; Li, X.; Yang, L. Exosome/antimicrobial peptide laden hydrogel wound dressings promote scarless wound healing through miR-21-5p-mediated multiple functions. Biomaterials 2024, 308, 122558. [Google Scholar] [CrossRef] [PubMed]
  306. Mangoni, M.L.; McDermott, A.M.; Zasloff, M. Antimicrobial peptides and wound healing: Biological and therapeutic considerations. Exp. Dermatol. 2016, 25, 167–173. [Google Scholar] [CrossRef] [PubMed]
  307. van der Weerden, N.L.; Hancock, R.E.; Anderson, M.A. Permeabilization of fungal hyphae by the plant defensin NaD1 occurs through a cell wall-dependent process. J. Biol. Chem. 2010, 285, 37513–37520. [Google Scholar] [CrossRef]
  308. Vassilopoulos, S.; Mylonakis, E. Avenues for antifungal drug discovery and development: Where to now? Expert Opin. Drug Discov. 2022, 17, 667–672. [Google Scholar] [CrossRef]
  309. Egessa, R. Antimicrobial peptides from freshwater invertebrate species: Potential for future applications. Mol. Biol. Rep. 2022, 49, 9797–9811. [Google Scholar] [CrossRef]
  310. Zasloff, M. Magainins, a class of antimicrobial peptides from Xenopus skin: Isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proc. Natl. Acad. Sci. USA 1987, 84, 5449–5453. [Google Scholar] [CrossRef]
  311. Valdez-Miramontes, C.E.; De Haro-Acosta, J.; Aréchiga-Flores, C.F.; Verdiguel-Fernández, L.; Rivas-Santiago, B. Antimicrobial peptides in domestic animals and their applications in veterinary medicine. Peptides 2021, 142, 170576. [Google Scholar] [CrossRef]
  312. Suarez-Jimenez, G.M.; Burgos-Hernandez, A.; Ezquerra-Brauer, J.M. Bioactive peptides and depsipeptides with anticancer potential: Sources from marine animals. Mar. Drugs 2012, 10, 963–986. [Google Scholar] [CrossRef]
  313. Nuti, R.; Goud, N.S.; Saraswati, A.P.; Alvala, R.; Alvala, M. Antimicrobial Peptides: A Promising Therapeutic Strategy in Tackling Antimicrobial Resistance. Curr. Med. Chem. 2017, 24, 4303–4314. [Google Scholar] [CrossRef]
  314. Huang, F.; He, J.; Zhang, Y.; Guo, Y. Synthesis of biotin-AMP conjugate for 5′ biotin labeling of RNA through one-step in vitro transcription. Nat. Protoc. 2008, 3, 1848–1861. [Google Scholar] [CrossRef] [PubMed]
  315. Brizuela, C.A.; Liu, G.; Stokes, J.M.; de la Fuente-Nunez, C. AI Methods for Antimicrobial Peptides: Progress and Challenges. Microb. Biotechnol. 2025, 18, e70072. [Google Scholar] [CrossRef] [PubMed]
  316. Huang, J.; Xu, Y.; Xue, Y.; Huang, Y.; Li, X.; Chen, X.; Xu, Y.; Zhang, D.; Zhang, P.; Zhao, J.; et al. Identification of potent antimicrobial peptides via a machine-learning pipeline that mines the entire space of peptide sequences. Nat. Biomed. Eng. 2023, 7, 797–810. [Google Scholar] [CrossRef] [PubMed]
  317. Ma, Y.; Guo, Z.; Xia, B.; Zhang, Y.; Liu, X.; Yu, Y.; Tang, N.; Tong, X.; Wang, M.; Ye, X.; et al. Identification of antimicrobial peptides from the human gut microbiome using deep learning. Nat. Biotechnol. 2022, 40, 921–931. [Google Scholar] [CrossRef]
  318. Hegde, A.R.; Paul, M.; Kumbham, S.; Roy, A.A.; Ahmad, S.F.; Parekh, H.; Biswas, S.; Mutalik, S. Ameliorative anticancer effect of dendrimeric peptide modified liposomes of letrozole: In vitro and in vivo performance evaluations. Int. J. Pharm. 2023, 648, 123582. [Google Scholar] [CrossRef]
  319. Bahar, A.A.; Liu, Z.; Totsingan, F.; Buitrago, C.; Kallenbach, N.; Ren, D. Synthetic dendrimeric peptide active against biofilm and persister cells of Pseudomonas aeruginosa. Appl. Microbiol. Biotechnol. 2015, 99, 8125–8135. [Google Scholar] [CrossRef]
  320. Batoni, G.; Casu, M.; Giuliani, A.; Luca, V.; Maisetta, G.; Mangoni, M.L.; Manzo, G.; Pintus, M.; Pirri, G.; Rinaldi, A.C.; et al. Rational modification of a dendrimeric peptide with antimicrobial activity: Consequences on membrane-binding and biological properties. Amino Acids 2016, 48, 887–900. [Google Scholar] [CrossRef]
  321. Han, Y.; Zhang, M.; Lai, R.; Zhang, Z. Chemical modifications to increase the therapeutic potential of antimicrobial peptides. Peptides 2021, 146, 170666. [Google Scholar] [CrossRef]
  322. He, S.; Yang, Z.; Li, X.; Wu, H.; Zhang, L.; Shan, A.; Wang, J. Boosting stability and therapeutic potential of proteolysis-resistant antimicrobial peptides by end-tagging β-naphthylalanine. Acta Biomater. 2023, 164, 175–194. [Google Scholar] [CrossRef]
  323. Marimuthu, S.K.; Nagarajan, K.; Perumal, S.K.; Palanisamy, S.; Subbiah, L. Structural stability of antimicrobial peptides rich in tryptophan, proline and arginine: A computational study. J. Biomol. Struct. Dyn. 2022, 40, 3551–3559. [Google Scholar] [CrossRef]
  324. Ghosh, A.; Zhao, Y. Site-Selective Functionalization of Molecularly Imprinted Nanoparticles to Recognize Lysine-Rich Peptides. Biomacromolecules 2024, 25, 6188–6194. [Google Scholar] [CrossRef] [PubMed]
  325. Shagaghi, N.; Palombo, E.A.; Clayton, A.H.; Bhave, M. Archetypal tryptophan-rich antimicrobial peptides: Properties and applications. World J. Microbiol. Biotechnol. 2016, 32, 31. [Google Scholar] [CrossRef] [PubMed]
  326. Du, Y.; Li, L.; Zheng, Y.; Liu, J.; Gong, J.; Qiu, Z.; Li, Y.; Qiao, J.; Huo, Y.X. Incorporation of Non-Canonical Amino Acids into Antimicrobial Peptides: Advances, Challenges, and Perspectives. Appl. Environ. Microbiol. 2022, 88, e0161722. [Google Scholar] [CrossRef] [PubMed]
  327. Svensen, N.; Walton, J.G.; Bradley, M. Peptides for cell-selective drug delivery. Trends Pharmacol. Sci. 2012, 33, 186–192. [Google Scholar] [CrossRef]
  328. Gallardo-Becerra, L.; Cervantes-Echeverría, M.; Cornejo-Granados, F.; Vazquez-Morado, L.E.; Ochoa-Leyva, A. Perspectives in Searching Antimicrobial Peptides (AMPs) Produced by the Microbiota. Microb. Ecol. 2023, 87, 8. [Google Scholar] [CrossRef]
  329. Bulger, E.M.; Maier, R.V.; Sperry, J.; Joshi, M.; Henry, S.; Moore, F.A.; Moldawer, L.L.; Demetriades, D.; Talving, P.; Schreiber, M.; et al. A Novel Drug for Treatment of Necrotizing Soft-Tissue Infections: A Randomized Clinical Trial. JAMA Surg. 2014, 149, 528–536. [Google Scholar] [CrossRef]
  330. Brown, K.L.; Poon, G.F.; Birkenhead, D.; Pena, O.M.; Falsafi, R.; Dahlgren, C.; Karlsson, A.; Bylund, J.; Hancock, R.E.; Johnson, P. Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses. J. Immunol. 2011, 186, 5497–5505. [Google Scholar] [CrossRef]
  331. Jang, W.S.; Li, X.S.; Sun, J.N.; Edgerton, M. The P-113 fragment of histatin 5 requires a specific peptide sequence for intracellular translocation in Candida albicans, which is independent of cell wall binding. Antimicrob. Agents Chemother. 2008, 52, 497–504. [Google Scholar] [CrossRef]
  332. Nibbering, P.H.; Ravensbergen, E.; Welling, M.M.; van Berkel, L.A.; van Berkel, P.H.; Pauwels, E.K.; Nuijens, J.H. Human lactoferrin and peptides derived from its N terminus are highly effective against infections with antibiotic-resistant bacteria. Infect. Immun. 2001, 69, 1469–1476. [Google Scholar] [CrossRef]
  333. Wang, Y.; Xia, K.; Wang, L.; Wu, M.; Sang, X.; Wan, K.; Zhang, X.; Liu, X.; Wei, G. Peptide-Engineered Fluorescent Nanomaterials: Structure Design, Function Tailoring, and Biomedical Applications. Small 2021, 17, e2005578. [Google Scholar] [CrossRef]
  334. Torres, M.D.T.; Sothiselvam, S.; Lu, T.K.; de la Fuente-Nunez, C. Peptide Design Principles for Antimicrobial Applications. J. Mol. Biol. 2019, 431, 3547–3567. [Google Scholar] [CrossRef] [PubMed]
  335. Chen, J.; Hao, D.; Mei, K.; Li, X.; Li, T.; Ma, C.; Xi, X.; Li, L.; Wang, L.; Zhou, M.; et al. In Vitro and In Vivo Studies on the Antibacterial Activity and Safety of a New Antimicrobial Peptide Dermaseptin-AC. Microbiol. Spectr. 2021, 9, e0131821. [Google Scholar] [CrossRef] [PubMed]
  336. Pinilla, G.; Coronado, Y.T.; Chaves, G.; Muñoz, L.; Navarrete, J.; Salazar, L.M.; Taborda, C.P.; Muñoz, J.E. In Vitro Antifungal Activity of LL-37 Analogue Peptides against Candida spp. J. Fungi 2022, 8, 1173. [Google Scholar] [CrossRef] [PubMed]
  337. Luo, Y.; McLean, D.T.; Linden, G.J.; McAuley, D.F.; McMullan, R.; Lundy, F.T. The Naturally Occurring Host Defense Peptide, LL-37, and Its Truncated Mimetics KE-18 and KR-12 Have Selected Biocidal and Antibiofilm Activities Against Candida albicans, Staphylococcus aureus, and Escherichia coli In vitro. Front. Microbiol. 2017, 8, 544. [Google Scholar] [CrossRef]
  338. Wang, B.; Lin, P.; Zhong, Y.; Tan, X.; Shen, Y.; Huang, Y.; Jin, K.; Zhang, Y.; Zhan, Y.; Shen, D.; et al. Explainable deep learning and virtual evolution identifies antimicrobial peptides with activity against multidrug-resistant human pathogens. Nat. Microbiol. 2025, 10, 332–347. [Google Scholar] [CrossRef]
  339. Duan, X.P.; Qin, B.D.; Jiao, X.D.; Liu, K.; Wang, Z.; Zang, Y.S. New clinical trial design in precision medicine: Discovery, development and direction. Signal Transduct. Target. Ther. 2024, 9, 57. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Zhang, Q.; Choi, K.; Wang, X.; Xi, L.; Lu, S. The Contribution of Human Antimicrobial Peptides to Fungi. Int. J. Mol. Sci. 2025, 26, 2494. https://doi.org/10.3390/ijms26062494

AMA Style

Zhang Q, Choi K, Wang X, Xi L, Lu S. The Contribution of Human Antimicrobial Peptides to Fungi. International Journal of Molecular Sciences. 2025; 26(6):2494. https://doi.org/10.3390/ijms26062494

Chicago/Turabian Style

Zhang, Qiaoxi, Kitman Choi, Xiaoyue Wang, Liyan Xi, and Sha Lu. 2025. "The Contribution of Human Antimicrobial Peptides to Fungi" International Journal of Molecular Sciences 26, no. 6: 2494. https://doi.org/10.3390/ijms26062494

APA Style

Zhang, Q., Choi, K., Wang, X., Xi, L., & Lu, S. (2025). The Contribution of Human Antimicrobial Peptides to Fungi. International Journal of Molecular Sciences, 26(6), 2494. https://doi.org/10.3390/ijms26062494

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop