RRC ID 32726
Author Nishimura S, Tokukura M, Ochi J, Yoshida M, Kakeya H.
Title Balance between exocytosis and endocytosis determines the efficacy of sterol-targeting antibiotics.
Journal Chem Biol
Abstract Antifungals targeting membrane ergosterol are longstanding, yet indispensable drugs in clinical use. However, the mechanisms by which the cellular membrane domains recognized by these antibiotics are generated remain largely unknown. Here, we demonstrate that the balance between endocytosis and exocytosis in membrane trafficking is a critical factor in the action of sterol-targeting antibiotics. When fission yeast cells were treated with manumycin A, cellular binding and the action of the antifungals filipin, amphotericin B, and theonellamides, all of which are ergosterol-binders, were abolished. Additionally, manumycin A treatment attenuated Cdc42 activity and inhibited exocytosis, while endocytosis was only moderately suppressed. Similar defects in membrane trafficking could be reproduced by heat shock and genetic perturbation, which also abolished the action of the antibiotics. We propose that exocytosis and endocytosis respectively supply and internalize the specific plasma membrane domains recognized by sterol-targeting antibiotics.
Volume 21(12)
Pages 1690-9
Published 2014-12-18
DOI 10.1016/j.chembiol.2014.10.014
PII S1074-5521(14)00380-9
PMID 25500221
MeSH Antifungal Agents / pharmacology* Drug Resistance, Bacterial / drug effects Endocytosis / drug effects* Exocytosis / drug effects* Heat-Shock Response / drug effects Membrane Microdomains / drug effects Membrane Microdomains / metabolism Polyenes / pharmacology Polyunsaturated Alkamides / pharmacology Schizosaccharomyces / cytology Schizosaccharomyces / drug effects Sterols / metabolism* cdc42 GTP-Binding Protein / metabolism
IF 5.915
Times Cited 7
Yeast NBRP ID: FY13493 (strain name: JX586) NBRP ID: FY13842 (strain name: CP18-8)