Quaternary Ammonium-Functionalized Chitosan as a Next-Generation Antifungal Platform: Chemistry, Mechanisms, and Therapeutic Applications

Fungal infection remains a significant therapeutic concern owing to the scarcity of drugs, resistance development, and high levels of toxicity of many conventional antifungals. In this regard, chitosan is one such natural polymer whose biocompatibility, biodegradability, and antimicrobial nature have made it the focus of scientific interest. However, the main problem lies in the polymer's limited aqueous solubility under physiological conditions and its poor efficacy against fungi. Thus, quaternary ammonium functionalization represents a convenient approach to solving the problem by introducing permanent positive charges into the molecular structure of chitosan, thereby improving water solubility, enabling membrane interactions, and conferring broad-spectrum antifungal activity. Such derivatives can exhibit strong interactions with the negatively charged surface of fungal cells, compromising membrane integrity and inhibiting biofilm formation. Apart from their antifungal activity, such compounds are also promising in local delivery systems, which include coatings, nanoparticles, hydrogels, and wound dressings. Considering their unique chemistry, such compounds appear quite promising for the development of novel antifungal biomaterials that can be adapted to different clinical and pharmaceutical needs. Overall, quaternary ammonium-modified chitosan could be considered a promising platform for the development of next-generation antifungal agents. This review offers a comprehensive discussion regarding the synthesis, mode of action, formulation advancements, safety profile, potential applications, and future directions of quaternary ammonium-functionalized chitosan derivatives as an antifungal agent, with an emphasis on artificial intelligence contributions to this area of research.