Differential activities of three families of specific beta(1,3)glucan synthase inhibitors in wild-type and resistant strains of fission yeast.
Three specific β(1,3)glucan synthase (GS) inhibitor families, papulacandins, acidic terpenoids, and echinocandins, have been analyzed in Schizosaccharomyces pombe wild-type and papulacandin-resistant cells and GS activities. Papulacandin and enfumafungin produced similar in vivo effects, different from that of echinocandins. Also, papulacandin was the strongest in vitro GS inhibitor (IC(50) 10(3)-10(4)-fold lower than with enfumafungin or pneumocandin), but caspofungin was by far the most efficient antifungal because of the following. 1) It was the only drug that affected resistant cells (minimal inhibitory concentration close to that of the wild type). 2) It was a strong inhibitor of wild-type GS (IC(50) close to that of papulacandin). 3) It was the best inhibitor of mutant GS. Moreover, caspofungin showed a special effect for two GS inhibition activities, of high and low affinity, separated by 2 log orders, with no increase in inhibition. pbr1-8 and pbr1-6 resistances are due to single substitutions in the essential Bgs4 GS, located close to the resistance hot spot 1 region described in Saccharomyces and Candida Fks mutants. Bgs4(pbr)(1-8) contains the E700V change, four residues N-terminal from hot spot 1 defining a larger resistance hot spot 1-1 of 13 amino acids. Bgs4(pbr)(1-6) contains the W760S substitution, defining a new resistance hot spot 1-2. We observed spontaneous revertants of the spherical pbr1-6 phenotype and found that an additional A914V change is involved in the recovery of the wild-type cell shape, but it maintains the resistance phenotype. A better understanding of the mechanism of action of the antifungals available should help to improve their activity and to identify new antifungal targets.
Instituto de Microbiología Bioquímica, Consejo Superior de Investigaciones Científicas/Universidad de Salamanca, 37007 Salamanca, Spain.
Ivone M
IM
Martins
Juan C G
JC
Cortés
Javier
J
Muñoz
M Belén
MB
Moreno
Mariona
M
Ramos
José A
JA
Clemente-Ramos
Angel
A
Durán
Juan C
JC
Ribas
D000617:Aminoglycosides / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D025141:Drug Resistance, Fungal / Q000235:genetics*; D054714:Echinocandins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D020125:Mutation, Missense; D012568:Schizosaccharomyces / Q000201:enzymology; D029702:Schizosaccharomyces pombe Proteins / Q000037:antagonists & inhibitors*; D013729:Terpenes / Q000494:pharmacology
D000617:Aminoglycosides; D000935:Antifungal Agents; D054714:Echinocandins; D004791:Enzyme Inhibitors; D029702:Schizosaccharomyces pombe Proteins; D013729:Terpenes; C014732:papulacandins; D005964:Glucosyltransferases; C040232:glucan synthase