1,3-β-glucan synthase

1,3-β-glucan synthase is a multi-subunit enzyme complex located in the fungal plasma membrane, encoded by the FKS gene family (FKS1 being the catalytic subunit in most species). It catalyzes polymerization of UDP-glucose into β-(1,3)-glucan polymers, which along with chitin and mannoproteins form the structural scaffold of the fungal cell wall, providing rigidity and protection against osmotic lysis. Because this enzyme and the glucan polymer it produces have no mammalian counterpart (human cells lack a cell wall), it is an ideal selective antifungal target with a favorable safety profile. Echinocandins (caspofungin, micafungin, anidulastatin) are noncompetitive inhibitors of this enzyme, leading to disruption of cell wall integrity, osmotic instability, and fungal cell lysis—fungicidal against Candida species and fungistatic against Aspergillus. Clinically, echinocandins are first-line for invasive candidiasis (including azole-resistant and fluconazole-resistant strains) and are used as salvage therapy for invasive aspergillosis. They are administered intravenously due to poor oral bioavailability. Resistance can arise from FKS gene mutations altering the enzyme's drug-binding site, notably seen in some Candida glabrata and Candida auris strains, which is a growing clinical concern. Notably, Cryptococcus neoformans and Mucorales (agents of mucormycosis) are intrinsically resistant to echinocandins due to differences in cell wall composition or enzyme susceptibility, so these drugs are not used for those infections.