Nikkomycin Z supersensitivity of an echinocandin-resistant mutant of Saccharomyces cerevisiae.
Echinocandins and nikkomycins are antibiotics that inhibit the synthesis of the essential cell wall polysaccharide polymers 1,3-beta-glucan and chitin, respectively. Some 40 echinocandin-resistant Saccharomyces cerevisiae mutants were isolated and assigned to five complementation groups. Four complementation groups contained mutants with 38 recessive mutations. The fifth complementation group comprised mutants with one dominant mutation, etg1-3 (strain MS10), and one semidominant mutation, etg1-4 (strain MS14). MS10 and MS14 are resistant to the semisynthetic pneumocandin B, L-733,560, and to aculeacin A but not to papulacandin. In addition, microsomal membranes of both mutant strains contain 1,3-beta-glucan synthase activity that is resistant to L-733,560 but not to papulacandin. Furthermore, MS14 is also supersensitive to nikkomycin Z. The echinocandin resistance and the nikkomycin Z supersensitivity of MS14 cosegregated in genetic crosses. The wild-type gene (designated ETG1 [C. Douglas, J. A. Marrinan, and M. B. Kurtz, J. Bacteriol. 176:5686-5696, 1994, and C. Douglas, F. Foor, J. A. Marrinan, N. Morin, J. B. Nielsen, A. Dahl, P. Mazur, W. Baginsky, W. Li, M. El-Sherbeini, J. A. Clemas, S. Mandala, B. R. Frommer, and M. B. Kurtz, Proc. Natl. Acad. Sci. USA, in press]) was isolated from a genomic library in the plasmid YCp50 by functional complementation of the nikkomycin Z supersensitivity phenotype. The cloned DNA also partially complements the echinocandin resistance phenotype, indicating that the two phenotypes are due to single mutations. The existence of a single mutation, in MS14, simultaneously affecting sensitivity to a glucan synthase inhibitor and a chitin synthase inhibitor implies a possible interaction between the two polymers at the cell surface.
el-Sherbeini
M
M
Microbial Chemotherapeutics and Molecular Genetics, Merck Research Laboratories, Rahway, New Jersey 07065.
Clemas
J A
JA
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D054714:Echinocandins; D005656:Fungal Proteins; D005964:Glucosyltransferases / Q000378:metabolism; D008565:Membrane Proteins; D009154:Mutation; D010455:Peptides; D010456:Peptides, Cyclic; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; C089367:L 733560; D008565:Membrane Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D029702:Schizosaccharomyces pombe Proteins; C011952:nikkomycin; C007572:echinocandin B; D005964:Glucosyltransferases; C020570:1,3-beta-glucan synthase