**1. Introduction**

Fungal infections and fungal contamination have become an important worldwide public health problem with a considerable impact on human morbidity and mortality. Immunosuppression, cancer treatment, and immunological dysfunctions result in disseminated or systemic fungal diseases, that might evolve into a life-threatening condition. In recent years, mycoses have increased their incidence, thus, the development of novel targeted therapeutics is an important challenge to treat them. Changes in etiology, including the emergence of new pathogens, resistance to antifungals, and opportunistic and immunosuppressive factors that many patients experience, add to the difficulties in diagnosing and treating fungal infections, a fact that increases costs in the health sector [1].

**Citation:** Martínez-Montelongo, J.H.; Medina-Ramírez, I.E.; Romo-Lozano, Y.; González-Gutiérrez, A.; Macías-Díaz, J.E. Development of Nano-Antifungal Therapy for Systemic and Endemic Mycoses. *J. Fungi* **2021**, *7*, 158. https://doi.org/ 10.3390/jof7020158

Academic Editor: Kamel A. Abd-Elsalam

Received: 10 December 2020 Accepted: 18 February 2021 Published: 23 February 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

*Sporothrix schenckii* is a widely distributed dimorphic fungus that is mainly recovered from environmental samples (plant or soil). It can cause sporotrichosis, which is a subcutaneous mycosis, with a subacute or chronic course in humans and other animals, and like the fungus, it has a wide geographical distribution. The infection usually occurs because of the traumatic inoculation of fungal conidia or fragments of hyphae, corresponding to its mycelial morphotype, into the skin or subcutaneous tissue. The clinical outcome of the infection depends on the immune response of the host, resulting in severe disseminated disease with visceral and osteoarticular involvement in immunocompromised individuals, particularly people with AIDS [2]. In infected tissue, the fungus differentiates into the pathogenic yeast form and may spread to other tissue. In addition, it can form resistance structures such as biofilms [3]. The gold standard for the treatment of the subcutaneous disease is itraconazole, although, in Mexico and some other underdeveloped countries, potassium iodide is still used, due to its low cost and safety.

*Candida albicans* is a pathogenic and opportunistic fungus responsible for numerous diseases. It is one of the most common causes of hospital-acquired systemic infections due to its adhesive and invasive properties, and its capability to form biofilms. The capacity of *C. albicans* to form biofilms increases their resistance to antifungal therapy and the ability of the yeast cells within the biofilm consortium to withstand host immune response [4]. Miconazole and fluconazole are commonly used for candidiasis treatment; however, side deleterious effects, fungal resistance, and relapse cases have been observed with the use of these anti-fungal agents.

As previously mentioned, antifungal therapy for systemic mycosis is limited, most of the time expensive and causes important toxic effects. Nanotechnology has become an interesting strategy to improve the efficacy and specificity of traditional antifungal drugs, since it allows lower toxicity, better bio-distribution, drug targeting, potent activity, and broad antifungal spectrum. Nanotechnology has positively impacted the advances in the development of novel strategies for the cure of infectious diseases. For instance, it has been demonstrated that trypanocidal therapy based on nano-systems, renders higher accessibility, improved selectivity, and specific delivery of the active principle to intracellular targets [5]. Different nanomaterials have been evaluated for the development of antimicrobial agents: Metallic nanoparticles (Ag, Cu, Au, Al), metal oxides (ZnO, TiO2, Fe3O4, CoFe2O4), fullerenes, carbon nanotubes, antimicrobial peptides and chitosan [6]. Lately, the use of CuI NPs was shown to inhibit the growth of Gram (+) and Gram (-) bacteria [7].

Biopolymers are valuable and flexible materials for biomedical and pharmaceutical applications. Their use as an excipient has increased since stable colloidal suspensions of different nanostructured materials can be formulated. In addition to the colloidal stability, the biopolymer might enhance the therapeutic efficacy of a compound. For example, chitosan composites are of interest due to the bioactivity of the polymer [8]. Chitosan has been investigated for its antimicrobial activity. This is shown by its multiple mechanisms: damage to peptidoglycan and/or cell membrane, damage to DNA or inhibition on the synthesis of mRNA, decreases the metalloproteinase activity of the microorganisms by metal chelation [9]. Formulations that involve the use of chitosan and nanoparticles exhibit increased surface area. Also, at physiological pH values, an increased density of positive charge on the surface of the composite favors the interaction to negatively charged biomolecules on the cell walls of microorganisms. This increases its antimicrobial activity. In this study, Copper (I) Iodide (CuI)-Arabic Gum (CuI@AG) and CuI-Chitosan (CuI@Ch) composites were prepared and evaluated for the inhibition of biofilm-forming pathogenic fungi (*S. schenckii*, *C. albicans*).

CuI is an interesting material that has found important industrial and biomedical applications [7,10,11]. Previous studies from our research group have demonstrated the antimicrobial activity of different metal oxide nanostructured materials [12–18]. We have also reported that the toxicity of metallic nanostructures is partly due to the lixiviation of ions to the medium, observing a direct correlation of toxicity and ion concentration. We explore the use of hybrid materials, to reduce toxicity and increase bio-activity (in this particular case, anti-fungal activity). In this work, we report on the synthesis, characterization, and antifungal activity of CuI composites. The composite under study contains three elements (Cu, I, chitosan) that show antifungal activity, which facilitates their administration at low doses. Moreover, the components of the composite exhibit activity under different mechanisms limiting the capacity of the pathogen to overcome their bioactivity.
