Antifungals blocking cell wall polysaccharide

PARK, STEVEN; GARCIA-EFFRON, GUILLERMO; PERLIN, DAVID S.

Biarritz (France)

Congreso; The first international fungal / plant cell wall meeting; 2008

The echinocandin antifungal drugs are the first new class compounds that target the fungal cell wall by blocking beta-1,3-D-glucan synthase (GS). These compounds act largely with non-competitive inhibition kinetics. Membranebound GS is 10-fold less sensitive to drug relative to detergent-extracted and highly enriched product entrapped enzyme. Resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two “hot-spot” regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by one thousand-fold or more. Resistant glucan synthase enzymes show normal Km (0.16 mM) values supporting the notion that the site of action of echinocandins is independent of substrate binding. (0.16 mM) values supporting the notion that the site of action of echinocandins is independent of substrate binding.