Fungal Drug Response and Antimicrobial Resistance

Abstract

Antifungal resistance is a growing concern as it poses a significant threat to public health. Fungal infections are a significant cause of morbidity and mortality, especially in immunocompromised individuals. The limited number of antifungal agents and the emergence of resistance have led to a critical need to understand the mechanisms of antifungal drug resistance. This review provides an overview of the importance of antifungal resistance, the classes of antifungal agents, and their mode of action. It highlights the molecular mechanisms of antifungal drug resistance, including alterations in drug modification, activation, and availability. In addition, the review discusses the response to drugs via the regulation of multidrug efflux systems and antifungal drug-target interactions. We emphasize the importance of understanding the molecular mechanisms of antifungal drug resistance to develop effective strategies to combat the emergence of resistance and highlight the need for continued research to identify new targets for antifungal drug development and explore alternative therapeutic options to overcome resistance. Overall, an understanding of antifungal drug resistance and its mechanisms will be indispensable for the field of antifungal drug development and clinical management of fungal infections.

Keywords: antifungal drugs; antifungal resistance; multidrug efflux; pathogenic fungi; pleiotropic drug response.

Figure 1

Mechanisms of action of traditional and novel antifungal drugs. Representative compounds are indicated for each class. FUMP = 5-fluorouridylic acid; Fcy1, Fca1 = cytosine deaminases; Fur1 = Uracil phosphoribosyltransferase; Ac-Phosphatidyl inositol = Acyl-Phosphatidyl inositol; GPI = Glycosylphosphatidyl inositol; DHODH = Dihydroorotate dehydrogenase.

Figure 2

The fungal pleiotropic drug resistance (PDR). Upper panel: General features of PDR regulation. Different xenobiotic molecules, including antibiotic drugs, are recognized by transcriptional activators (Pdr-TFs) via their xenobiotic binding domains (XBD). Pdr-TFs bound at pleiotropic drug resistance promoter elements (PDRE) stimulate via their transactivation domains (AD) the expression of PDR, MDR, or MFS genes encoding plasma membrane transporters of the pleiotropic drug resistance, multidrug resistance, or major facilitator superfamilies. Lower panel: molecular mechanisms leading to antifungal drug resistance via the PDR system.