3.

Mechanisms of action of antifungal drug classes and the associated principal forms of acquired resistance. (a) Polyene resistance: (1) altered cell membrane permeability, (2) loss-of-function mutations in ergosterol biosynthesis genes, (3) changes in membrane sterol composition, and (4) induction of genes promoting tolerance and stress response pathways. Mechanism of action (MA): formation of a polyene-ergosterol complex, decreasing the protein gradient and resulting in osmotic lysis. (b) Azole resistance: (1) point mutations in the gene encoding the target (lanosterol 14α-demethylase), (2) target overproduction, (3) efflux pump overproduction or hyperactivity, (4) hypermutation in the target and housekeeping genes, and (5) heteroresistance and aneuploidy. MA: lanosterol 14α-demethylase inhibition. (c) Pyrimidine analog resistance: (1) target gene (cytosine deaminase and flucytosine resistance) mutations. MA: RNA and DNA synthesis inhibition. (d) Allylamine resistance: (1) target gene (squalene epoxidase) mutations, (2) antifungal compound degradation, (3) efflux pump overproduction or hyperactivity, and (4) induction of stress response pathways. MA: squalene epoxidase inhibition. (e) Echinocandin resistance: (1) point mutations in the gene encoding the target (1,3-β-glucan synthase subunit [FKS1]) and (2) cell wall stress response pathway activation. MA: 1,3-β-glucan synthase inhibition. (f) Triterpenoid resistance: (1) point mutations in the gene encoding the target (1,3-β-glucan synthase subunit [FKS2]) and (2) unknown responses to cell wall stress. MA: 1,3-β-glucan synthase inhibition. 5-FU: 5-fluorouridine, CYP51A/ERG11: lanosterol 14α-demethylase, ERG: ergosterol biosynthesis genes, FCY: cytosine deaminase gene, FCA: flucytosine resistance gene, FdUMP: 5′-fluoro deoxyuridine monophosphate, Fks1p and Fks2p: 3-β-glucan synthase subunits, FUR1: uracil phosphoribosyltransferase gene, hsp: heat shock protein gene, Hsp90: heat shock protein 90, MSH2: azole resistance gene, salA: salicylate 1-monooxygenase gene SalA: salicylate 1-monooxygenase, sqle: squalene epoxidase gene. Asterisks indicate mutations. The figure is adapted from Fisher et al. and updated using information presented in Martinez-Rossi et al., and with the original literature findings. Panels (a)–(f) are adapted by permission from Macmillan Publishers Ltd.: NATURE REVIEWS MICROBIOLOGY Fisher, M.C. et al. Tackling the emerging threat of antifungal resistance to human health. Nat. Rev. Microbiol. 2022, 20(9), 557–571, copyright 2022.