Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

• DOI: 10.1074/jbc.m110.174300
• Publication Date: 2010-11-30T05:04:41Z
• Authors: Ivone M. Martins; Juan C.G. Cortés; Javier Muñoz; M. Belén Moreno; Mariona Ramos; José A. Clemente-...; Angel Durán; Juan C. Ribas
• Keywords: Membrane enzymes; Antifungals; 0303 health sciences; Antifungal Agents; Terpenes; Fks proteins; Mutation, Missense; Enzyme inhibitors; Yeast; Glucan; Echinocandins; Inhibitory Concentration 50; 03 medical and health sciences; Aminoglycosides; Antibiotics; Caspofungin; Drug Resistance, Fungal; Glucosyltransferases; Schizosaccharomyces; Glucan synthase; Schizosaccharomyces pombe Proteins; Enzyme Inhibitors; Cell walls

Three specific β(1,3)glucan synthase (GS) inhibitor families, papulacandins, acidic terpenoids, and echinocandins, have been analyzed in Schizosaccharomyces pombe wild-type papulacandin-resistant cells GS activities. Papulacandin enfumafungin produced similar vivo effects, different from that of echinocandins. Also, papulacandin was the strongest vitro (IC50 103–104-fold lower than with or pneumocandin), but caspofungin by far most efficient antifungal because following. 1) It only drug affected resistant (minimal inhibitory concentration close to wild type). 2) a strong papulacandin). 3) best mutant GS. Moreover, showed special effect for two inhibition activities, high low affinity, separated 2 log orders, no increase inhibition. pbr1-8 pbr1-6 resistances are due single substitutions essential Bgs4 GS, located resistance hot spot 1 region described Saccharomyces Candida Fks mutants. Bgs4pbr1-8 contains E700V change, four residues N-terminal defining larger 1-1 13 amino acids. Bgs4pbr1-6 W760S substitution, new 1-2. We observed spontaneous revertants spherical phenotype found an additional A914V change is involved recovery cell shape, it maintains phenotype. A better understanding mechanism action antifungals available should help improve their activity identify targets.