Reshaping Echinocandin Antifungal Drugs To Circumvent Glucan Synthase Point‐Mutation‐Mediated Resistance

Abstract

Echinocandins are a class of antifungal drugs that inhibit the activity of the β‐(1,3)‐glucan synthase complex, which synthesizes fungal cell wall β‐(1,3)‐glucan. Echinocandin resistance is linked to mutations in the FKS gene, which encodes the catalytic subunit of the glucan synthase complex. We present a molecular docking‐based model that provides insights into how echinocandins interact with the target Fks protein: echinocandins form a ternary complex with both Fks and membrane lipids. We used reductive dehydration of alcohols to generate dehydroxylated echinocandin derivatives and evaluated their potency against a panel of Candida pathogens constructed by introducing resistance‐conferring mutations in the FKS gene. We found that removing the hemiaminal alcohol, which drives significant conformational alterations in the modified echinocandins, reduced their efficacy. Conversely, eliminating the benzylic alcohol of echinocandins enhanced potency by up to two orders of magnitude, in a manner dependent upon the resistance‐conferring mutation. Strains that have developed resistance to either rezafungin, the most recently clinically approved echinocandin, or its dehydroxylated derivative RZF‐1, exhibit high resistance to rezafungin while demonstrating moderate resistance to RZF‐1.These findings provide valuable insights for combating echinocandin resistance via chemical modifications.

Structural and Biophysical Dynamics of Fungal Plasma Membrane Proteins and Implications for Echinocandin Action inCandida glabrata

“…It is also possible that echinocandins directly interact with lipid molecules within the binding pocket, and thereby modify GS enzymatic activity. Recent docking simulations have suggested that the lipophilic tail of echinocandins may form a ternary complex with these bound lipids 39 . Further studies will be necessary to determine the molecular details of these interactions and to understand how specific lipid molecules, such as sphingolipids and ergosterols, influence echinocandin activity and the development of antifungal resistance.…”

What is the role of microbial biotechnology and genetic engineering in medicine?

“…Most of the antifungal drugs of natural origin currently in clinical use belong to either the polyene class, such as amphotericin B, nystatin, and natamycin, or to the echinocandin class, which includes caspofungin, anidulafungin, and micafungin (Baginski & Czub, 2009 ; Houšť et al, 2020 ). Echinocandins, which are not fully natural, are a highly selective class of semisynthetic lipopeptides that inhibit the synthesis of 1,3‐β‐glucans, important constituents of the fungal cell wall (Jospe‐Kaufman et al, 2024 ). Due to their mechanism of action, which is analogous to β‐lactam antibiotics in bacteria (i.e., inhibition of cell wall synthesis), this class of compounds is often termed the “penicillin of antifungals.” Several new compounds with antifungal activity, both natural and synthetic (e.g., nikkomycin Z, griseofulvin, olorofim, rezafungin, fosmanogepix, ibrexafungerp, opelconazole, and encochleated), have been developed through various scientific research programs and are in the process of being approved by major regulatory agencies, such as the FDA (Boutin & Luong, 2024 ).…”