Search Results (63)

Wheat Fusarium head blight (FHB) is a globally prevalent and destructive fungal disease predominantly caused by Fusarium graminearum. Pydiflumetofen, a novel succinate dehydrogenase inhibitor (SDHI) fungicide, exhibits strong inhibitory activity against F. graminearum; however, the molecular regulatory mechanisms underlying the field-developed resistance in this pathogen remain poorly defined. In the present study, a field-evolved resistant isolate W24-039 and a sensitive isolate W24-016 were subjected to multi-omics analysis. The sequencing results identified compound mutations C89S/A93V in SdhC2, and A21T/S30F in SdhD of the resistant strain, which confer stable fungicide resistance without any detectable fitness costs. Physiological tests revealed that these target mutations sustain the homeostasis of succinate dehydrogenase (SDH) activity and intracellular ATP production. Following pydiflumetofen treatment, the sensitive isolate displayed remarkable declines in SDH activity, intracellular ATP content and deoxynivalenol (DON) biosynthesis, accompanied by markedly elevated cell membrane permeability. Transcriptomic sequencing uncovered 2221 differentially expressed genes (DEGs) in the sensitive strain under fungicide stress, and 2566 DEGs in the resistant isolate under the same conditions. The genes associated with detoxification and drug efflux, including cytochrome P450, glutathione S-transferase (GST), ABC and MFS transporters, were significantly upregulated in the resistant isolate. Metabolomic analysis indicated that differential metabolites were mainly enriched in the tricarboxylic acid (TCA) cycle, amino acid metabolism and membrane lipid biosynthesis pathways. The resistant strain maintained intact TCA cycle operation and accumulated high levels of pivotal metabolites such as phosphatidylcholine, unsaturated fatty acids and reduced glutathione. Integrated multi-omics analysis verified that the ABC transporter and glutathione metabolism pathways serve as core regulatory modules governing fungicide resistance. Collectively, F. graminearum develops resistance via the synergistic effects of SDH compound mutations, enhanced detoxification and efflux, and global metabolic remodeling, demonstrating that target-site mutation alone is not the sole driver of resistance, which is instead controlled by an intricate regulatory network involving multiple coordinated pathways. This study systematically characterizes the resistance regulatory network of F. graminearum against pydiflumetofen, and provides theoretical guidance for the rational application and sustainable field resistance management of this fungicide. Full article

Gram-negative bacteria pose a significant threat to global health due to their high prevalence, multidrug resistance, and association with various infections. Zinc, an essential trace element, plays a dual role in host–microbe interactions, being crucial for both host immune function and bacterial metabolism. Maintaining optimal zinc homeostasis is essential for effective host defense and microbial survival. We comprehensively examine the multifaceted roles of zinc in host–microbe interactions, particularly focusing on its implications for the pathogenicity of Gram-negative bacteria and host immunity. As part of nutritional immunity, hosts have evolved zinc-mediated antimicrobial strategies that manipulate metal availability at the host–pathogen interface, including zinc limitation that restricts bacterial access to this essential nutrient and zinc intoxication that exposes invading bacteria to cytotoxic zinc concentrations. In Gram-negative bacteria, zinc homeostasis, maintained through zinc transporters and efflux systems, critically governs bacterial virulence, biofilm formation, and survival under host-imposed nutritional immunity. By integrating current advances, this review highlights zinc homeostasis as a central determinant of host–pathogen interactions and a promising target for combating multidrug-resistant Gram-negative infections. Understanding these complex zinc-mediated mechanisms provides new perspectives for developing metal-targeted therapeutic strategies. Full article

Fungal infections represent an escalating global health challenge due to their increasing incidence, the emergence of multidrug-resistant pathogens, and the limited development of new antifungal agents. Therapeutic efficacy is compromised by mutations in drug targets, overexpression of efflux pumps, alterations in the ergosterol biosynthetic pathway, biofilm-associated tolerance, and extensive genomic plasticity. The growing prevalence of antifungal resistance and the limited availability of effective therapeutic options highlight the urgent need to strengthen epidemiological surveillance and accelerate research into innovative therapeutic strategies. In this review, we discuss the potential of lipid-based drug delivery systems (LDDSs) as a versatile strategy to optimize antifungal administration and overcome resistance mechanisms. Liposomes (LPs), solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), and lipid nanoparticles (LNPs) offer high biocompatibility, efficient encapsulation of hydrophobic compounds, structural stability, and controlled drug release. Their nanoscale properties facilitate penetration into biofilms, promote intracellular uptake, and reduce the impact of efflux-mediated drug extrusion, thereby improving cellular penetration and circumventing resistance pathways. In addition, LDDSs increase bioavailability, reduce toxicity, and promote drug accumulation within poorly accessible tissue compartments. Overall, LDDSs represent a promising approach to expand the therapeutic arsenal against both superficial and invasive fungal infections, particularly those caused by multidrug-resistant pathogens. Full article

The increasing prevalence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria represents a major global public health challenge. Among hospital-acquired infections (HAIs), ventilator-associated pneumonia (VAP) caused by non-fermenting Gram-negative pathogens, particularly the Acinetobacter baumannii-calcoaceticus complex, it is associated with limited therapeutic options and high mortality. Sulbactam–durlobactam is a novel combination consisting of sulbactam, a β-lactamase inhibitor with intrinsic activity against Acinetobacter spp., and durlobactam, a diazabicyclooctane β-lactamase inhibitor targeting Ambler class A, C, and D enzymes. This review summarizes current evidence on the pharmacological properties, clinical efficacy, and resistance mechanisms associated with this combination. Clinical trials have demonstrated that sulbactam–durlobactam is non-inferior to colistin in the treatment of infections caused by carbapenem-resistant A. baumannii, with a significantly lower risk of nephrotoxicity. The combination is generally well tolerated and represents a promising therapeutic option for difficult-to-treat infections. However, emerging resistance mechanisms, including PBP3 mutations, metallo-β-lactamase production, and efflux pump overexpression, may limit its long-term effectiveness. Further research is required to better understand resistance development and optimize clinical use. Full article

Background: Metallic and metal oxide nanoparticles are increasingly explored as antimicrobial biomaterials in endodontics due to their multi-target mechanisms of action, largely mediated by metal ion release (e.g., Ag⁺, Cu⁺). However, bacterial metal resistance systems, particularly efflux-related proteins, may influence their antimicrobial performance. This study aimed to analyze the prevalence and distribution of metal resistance-associated proteins in bacteria involved in endodontic infections using a bioinformatic approach. Methods: An in silico, cross-sectional bioinformatic analysis was conducted using publicly available genomes from the Bacterial and Viral Bioinformatics Resource Center (BV-BRC). Bacterial species associated with acute apical abscess (AAA), symptomatic apical periodontitis (SAP), asymptomatic apical periodontitis (AAP), and post-treatment apical periodontitis (PTAP) were included. The presence of selected metal resistance-related proteins (CutC, CopA, CzcA, CusA, SilA, P-type ATPase, and PA3920) was assessed using a binary presence/absence framework. Prevalence, group comparisons (Fisher’s exact test), and co-occurrence patterns (Phi coefficient) were analyzed. Results: Metal resistance-associated proteins were widely distributed across all infection types, with prevalence ranging from 70.0% to 82.9% and no significant differences between groups (p > 0.05). CutC was the most prevalent protein, followed by CopA and CzcA, whereas SilA and PA3920 were not detected. Correlation analysis revealed consistent co-occurrence patterns among key taxa, including Porphyromonas gingivalis, Fusobacterium nucleatum, and Prevotella spp. Conclusions: Metal resistance-related proteins are broadly distributed in endodontic microbiota, indicating a conserved genetic capacity for metal tolerance. These findings suggest that microbial resistance determinants may influence, but do not directly determine, the antimicrobial performance of nanoparticle-based biomaterials. This study provides a hypothesis-generating, bioinformatic framework to support the design and optimization of antimicrobial biomaterials, highlighting the need for experimental validation and integration of phenotypic and biofilm-based analyses. Full article

Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa rank among the most challenging pathogens due to increasing prevalence of multidrug-resistant (MDR) strains. These pathogens pose major risks to public health and food safety, earning their inclusion on the World Health Organization (WHO) priority list of MDR bacteria. While available conventional antibiotics are becoming less effective, natural products from plant extracts offer promising alternative and synergetic effects that can restore efficacy and lower required doses. Their antimicrobial activity is attributed to phytochemicals such as phenolic compounds and terpenoids acting via membrane disruption, efflux pump inhibition, biofilm interference, and cell protein disruption. Furthermore, phytochemicals in essential oils, such as carvacrol, thymol, and cinnamaldehyde, also exhibit antimicrobial and antioxidant activities. Their broad antimicrobial effects extend shelf life and enhance food safety, making them effective natural alternatives to synthetic preservatives. Moreover, advances in extraction and characterization techniques, including green solvents, spectrometry and hyphenated chromatographic methods, have improved recovery, identification and quantification. In addition, artificial intelligence (AI) emerges as a transformative tool to accelerate discovery, optimize compound screening, and predict synergistic interactions. Notwithstanding these advances, challenges persist in standardization, bioavailability, and clinical translation. Further studies are needed to isolate active compounds, elucidate mechanisms of action, validate combined use with conventional antibiotics and overcome formulation, delivery, sensory and regulatory hurdles. This review examines current knowledge of opportunities and limitations of plant-based antimicrobials against MDR pathogens supported by advances in extraction, characterization, and AI. Full article

Background/Objectives: Staphylococcus aureus, particularly methicillin-resistant strains, is a leading cause of severe pneumonia. Understanding local molecular epidemiology, including virulence gene profiles and antimicrobial resistance (AMR) mechanisms, is crucial for effective infection control. This pilot study aimed to characterize S. aureus isolates from pneumonia patients in Karaganda, Kazakhstan. Methods: We collected 48 respiratory samples from patients with pneumonia across three medical institutions. Bacterial identification was performed using MALDI-TOF MS. Antimicrobial susceptibility testing (AST) was carried out using European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Whole-genome sequencing of S. aureus isolates was conducted on an Ion Torrent S5 platform. Genomic analysis included multilocus sequence typing (MLST), identification of virulence and AMR genes, and phylogenetic reconstruction. Results: S. aureus was identified in 14.6% (n = 7) of pneumonia cases included in this study. All isolates (100%, n = 7) were phenotypically resistant to benzylpenicillin. The mecA gene was detected in 57.1% of isolates (n = 4), while phenotypic resistance to methicillin was observed in 28.6% (n = 2) of the isolates. Resistance to azithromycin (57.1%, n = 4) and levofloxacin (42.9%, n = 3) was observed among the isolates. Two isolates (28.6%) were multidrug-resistant (MDR). Genomic analysis revealed the prevalence of the ST22 clone (57.1%, n = 4) in the studied cohort. Other sequence types were ST97, ST8, and ST45 (14.3% each). Phylogenetic analysis showed clustering consistent with MLST profiles. All isolates carried a conserved core virulence arsenal, including hemolysin (hla, hlg), biofilm-forming genes (icaADBC), immune evasion genes (sak, scn), and iron acquisition genes (isd). The Panton–Valentine leukocidin (PVL) genes were detected in three isolates. AMR gene analysis revealed the ubiquitous presence of mepA and tetracycline efflux pump genes, along with regulatory genes (arlRS, mepR, mgrA). The blaZ and ermA genes were not detected despite high phenotypic resistance to penicillin and macrolides. Conclusions: This study reports the identification of the virulent and resistant ST22 S. aureus clone in pneumonia cases in Karaganda, Kazakhstan. The discordance between phenotypic and genotypic AMR profiles underscores the necessity for integrated diagnostic approaches. Full article

Background/Objectives: Integrons are genetic platforms that allow bacteria to acquire antimicrobial resistance (AMR) genes, making them a focal point for many AMR studies and surveillance programs. This study investigated how the prevalence of integrons (intI and attI genes) in third-generation cephalosporin-resistant E. coli (3GCR-Ec) varied across three different sources (i.e., healthy children, domestic animals and urinary tract infections). The study aimed to determine how different classes of AMR genes vary among 3GCR-Ec with integrons present versus those where integrons are absent. Methods: We analyzed 3GCR-Ec isolates collected from semirural parishes of Eastern Quito, Ecuador, that included: (1) 3GCR-Ec from healthy children (n = 946), (2) 3GCR-Ec from domestic animal species (n = 673), and 3GCR-Ec from patients with urinary tract infections (UTIs) (n = 138). Genomic analyses were performed for all 1757 sequences to determine how the presence and absence of integrons was associated with AMR gene carriage. Results: Among the total sequences of 3GCR-Ec evaluated across all datasets, nearly one-third (31%) were integron-negative. 3GCR-Ec from UTI patients, however, had a higher percentage containing integrons (79%). Across all sets of 3GCR-EC, integron-positive isolates carried an average of 10.3 (±3.0 SD) AMR genes versus 4.8 (±2.5 SD) AMR genes in integron-negative isolates. This study found that between 21% to 33% of 3GCR-Ec across the three different sources lacked integrons but maintained the ability to carry diverse classes of AMR genes, including beta-lactams, aminoglycosides, tetracyclines, and multidrug resistance mechanisms (e.g., general-purpose efflux pumps). Conclusions: While integrons were associated with greater AMR genes on average, the study highlights that solely relying on integrons for tracking drug-resistant bacteria misses a substantive portion of AMR that is present in integron-negative strains. Full article

Acinetobacter baumannii is a leading cause of healthcare-associated infections and is classified among the highest-priority antimicrobial-resistant pathogens. Its clinical success reflects the convergence of antimicrobial resistance (AMR) and biological traits that promote environmental persistence and transmission. Acinetobacter baumannii has undergone a remarkable transformation over the past few decades, evolving from a relatively obscure environmental bacterium into a globally recognized multidrug-resistant pathogen. Its prevalence in healthcare settings, particularly intensive care units, has made it a leading cause of ventilator-associated pneumonia, bloodstream infections, wound infections, and urinary tract infections. Beyond its antibiotic resistance, the bacterium’s ability to persist in hospital environments and adapt to host defences has amplified its clinical significance. Recent research has uncovered complex networks of virulence factors, regulatory systems, and metabolic strategies that enable A. baumannii to thrive in hostile environments and evade host immunity, providing new insights into its pathogenesis and potential therapeutic vulnerabilities. This review summarizes the main mechanisms underlying its pathogenicity, including desiccation tolerance, biofilm formation, disinfectant resistance, metal acquisition, motility, and the ability to enter viable but non-culturable states. In A. baumannii, AMR functions as a pathogenesis-adjacent trait, enhancing survival and clonal dissemination through genomic plasticity, resistance islands, efflux systems, and envelope remodeling. Key resistance pathways involve carbapenem-hydrolyzing oxacillinases, metallo-β-lactamases, permeability defects, and multidrug efflux, often coexisting within high-risk clones. From a clinical perspective, management of carbapenem-resistant strains requires accurate infection diagnosis, reliable susceptibility testing, site-specific and PK/PD-optimized therapy, and early reassessment. Overall, the success of A. baumannii reflects the integration of resistance and persistence within healthcare ecosystems, highlighting the need for coordinated strategies combining stewardship, infection control, improved diagnostics, and anti-biofilm or anti-virulence approaches. Full article

Mycoplasma pneumoniae is a significant pathogen responsible for community-acquired respiratory infections in children and adolescents, with the rising prevalence of macrolide-resistant M. pneumoniae (MRMP), particularly in Asia, presenting critical treatment challenges. Our previous study inferred that a macrolide efflux pump may contribute to macrolide resistance in M. pneumoniae in addition to the common point mutations in 23S rRNA gene. This study aimed to define the specific pump and confirm its role. Through comparative genomic analysis, we identified a candidate gene, MPN_080, encoding an ABC transporter permease, which was further characterized using phylogenetic analysis, AlphaFold-based structural modeling, and biochemical assays. Overexpression of MPN_080 from an erythromycin-resistant isolate in the erythromycin-sensitive M129 resulted in a significant increase in minimum inhibitory concentrations (MICs) from <0.125 µg/mL to 1 µg/mL, while similar overexpression of MPN_080 derived from M129 did not affect MICs. Notably, this resistance mechanism operates independently of M. pneumoniae virulence factors, as evidenced by unaltered colonization capacity in NCI-H292 cells and consistent immune response patterns across both strains. Our findings establish MPN_080 as a novel determinant of macrolide resistance functioning associated with enhanced ATPase activity. These insights into non-classical resistance mechanisms may guide future diagnostic and therapeutic strategies against MRMP. Full article

Klebsiella pneumoniae is a prominent pathogen implicated in a wide range of infections, including pneumonia, urinary tract infections, and septicemia. Its ability to acquire and disseminate antibiotic resistance, coupled with the rising prevalence of hypervirulent strains, represents a significant public health threat. Understanding the molecular basis of drug resistance can guide the design and development of effective treatment strategies. Antimicrobial resistance (AMR) in these bacteria is a complicated process and cannot be attributed to a single resistance mechanism. K. pneumoniae develops resistance to antibiotics through a variety of mechanisms, ranging from single molecular mechanisms to complex interactions, where molecular synergy exacerbates resistance. This review summarizes the current understanding of the molecular mechanisms that contribute to the drug resistance and virulence of this pathogen. Key antibiotic resistance mechanisms include drug inactivation via B-lactamases and carbapenemases, membrane remodeling, efflux pump systems, such as AcrAB-TolC and OqxAB, and biofilm formation facilitated by quorum sensing. Additionally, the role of ribosomal changes in resistance is highlighted. This review also examines the mechanisms of virulence, emphasizing fimbriae, iron acquisition systems, and immune evasion strategies. Understanding these mechanisms of drug resistance and virulence is crucial for remodeling existing antibiotics and developing new therapeutic strategies. Full article

The emergence of multidrug-resistant (MDR) bacterial pathogens has heightened the urgency for novel antibacterial agents. The bacterial cell wall usually comprises peptidoglycan, which presents a prime target for antibacterial drug development due to its indispensable role in maintaining cellular integrity. Conventional antibiotics such as β-lactams and glycopeptides hinder peptidoglycan synthesis through competitive binding of penicillin-binding proteins (PBPs) and sequestration of lipid-linked precursor molecules. Nevertheless, prevalent resistance mechanisms including target modification, β-lactamase hydrolysis, and multi-drug efflux pumps have limited their clinical utility. This comprehensive analysis explicates the molecular machinery underlying bacterial cell wall assembly, evaluates both explored and unexplored enzymatic nodes within this pathway, and highlights the transformative impact of high-resolution structural elucidation in accelerating structure-guided drug discovery. Novel targets such as GlmS, GlmM, GlmU, Mur ligases, D,L-transpeptidases are assessed for their inclusiveness for the discovery of next-generation antibiotics. Additionally, cell wall inhibitors are also examined for their mechanisms of action and evolutionary constraints on MDR development. High-resolution crystallographic data provide valuable insights into molecular blueprints for structure-guided optimization of pharmacophores, enhancing binding affinity and circumventing resistance determinants. This review proposes a roadmap for future innovation, advocating for the convergence of computational biology platforms, machine learning-driven compound screening, and nanoscale delivery systems to improve therapeutic efficacy and pharmacokinetics. The synergy of structural insights and cutting-edge technologies offers a multidisciplinary framework for revitalizing the antibacterial arsenal and combating MDR infections efficiently. Full article

Oral squamous cell carcinoma (OSCC) remains a highly prevalent and aggressive malignancy with limited improvements in survival rates. One of the major obstacles to successful treatment is the development of chemoresistance, which contributes to recurrence, metastasis, and treatment failure. This narrative review aims to integrate current evidence on the molecular and cellular mechanisms that drive chemoresistance in OSCC and to delineate how these processes converge under therapeutic pressure. A structured search was performed to identify relevant studies addressing chemoresistance in OSCC, focusing on preclinical and translational evidence. Multiple interconnected mechanisms have been implicated in driving resistance in OSCC, including epigenetic alterations, deregulated signaling pathways, cancer stem cell plasticity, epithelial–mesenchymal transition (EMT), interactions with the tumor microenvironment (TME), drug efflux mediated by ATP-binding cassette (ABC) transporters, and enhanced DNA damage response. In combination, these mechanisms support tumor persistence and limit effective antitumor immunity. Emerging strategies such as epigenetic modulators, signaling pathway inhibitors, immunomodulation, and nanomedicine-based delivery systems have shown promising results in preclinical models. By highlighting convergent resistance networks, this integrative perspective supports the rational design of combination therapies and biomarker-guided strategies aimed at overcoming chemoresistance in OSCC. Full article

Uropathogenic Escherichia coli (UPEC) is the leading cause of urinary tract infections (UTIs) and a major contributor to the global antimicrobial resistance crisis. The increasing prevalence of multidrug-resistant (MDR) strains, including expanded-spectrum β-lactamases (ESBL) and carbapenemase-producing isolates, severely limits treatment options. This review provides an overview on the key molecular mechanisms of UPEC antibiotic resistance, such as enzymatic inactivation, target-site mutations, efflux pump activity, and biofilm formation. Beyond conventional antibiotics, special emphasis is placed on phytochemical strategies as promising alternatives. Flavonoids, alkaloids, terpenoids, and essential oils exhibit antibacterial, anti-adhesive, and antibiofilm properties. These natural bioactive compounds modulate motility, suppress fimbrial expression, inhibit quorum sensing, and enhance antibiotic efficacy, acting both as standalone agents and as adjuvants. Current in vitro and in vivo studies highlight the potential of plant-derived compounds and biologically based therapies to combat UPEC. However, challenges related to standardization, bioavailability, and clinical validation remain unresolved. Integrating molecular mechanistic insights with advanced phytochemical research may offers a sustainable and effective strategy for mitigating UPEC antibiotic resistance. Full article

Background: Efflux-mediated macrolide resistance represents an emerging threat in Streptococcus infections globally. However, molecular epidemiological data from the Gulf region, particularly the United Arab Emirates (UAE), remain limited. This study addresses this knowledge gap by investigating efflux pump resistance mechanisms in clinical Streptococcus isolates. Methods: A cross-sectional study analyzed 100 clinical isolates (99 Streptococcus and 1 Enterococcus) from Thumbay Hospital, Ajman, UAE (October–December 2024). Antimicrobial susceptibility testing for minimum inhibitory concentration (MIC) determination was performed using the DxM 1096 MicroScan WalkAway system (Beckman Coulter Inc., Brea, CA, USA; LabProv4.42). PCR detected mef(A/E), msr(D), and tet(K) resistance genes with sequencing confirmation. Comparative genomic analysis was performed using a total of 30 publicly available Streptococcus genomes: 15 from India and 15 from Saudi Arabia. Statistical analysis employed chi-square tests, Fisher’s exact tests, and multivariate logistic regression with Bonferroni correction (α = 0.05). Results: Among the isolates, erythromycin resistance occurred in 39 isolates (39%, 95% CI: 29.4–49.2%) and clindamycin resistance in 31 isolates (31%, 95% CI: 22.1–40.9%). The mef(A/E) gene was detected in 31 isolates (31%, 95% CI: 22.1–40.9%), and msr(D) in 3 isolates (3%, 95% CI: 0.6–8.5%), with co-occurrence in 3 isolates (3%). No isolates harbored tet(K). Multivariate analysis identified mef(A/E) as the strongest predictor of macrolide resistance (OR = 18.7, 95% CI: 7.9–44.2, p < 0.001). Regional comparison revealed significant differences: mef(A/E) prevalence was 31% (UAE), 87% (India), and 0% (Saudi Arabia) (p < 0.001). Conclusions: This study provides the first molecular characterization of efflux-mediated macrolide resistance in UAE Streptococcus isolates. The predominance of mef(A/E)-mediated resistance with confirmed efflux activity highlights the clinical significance of active surveillance and targeted antimicrobial stewardship in the region. Full article