期刊
FEMS MICROBIOLOGY LETTERS
卷 231, 期 2, 页码 177-184出版社
OXFORD UNIV PRESS
DOI: 10.1016/S0378-1097(03)00931-5
关键词
mode of action; Staphylococcus aureus; antisense RNA; FabI inhibitor
类别
Validation of antibiotic mode of action in whole bacterial cells is a key step for antibiotic drug discovery. In this study, one potential drug target, enoyl-acyl carrier protein reductase (FabI), an essential enzyme in the fatty acid biosynthesis pathway, was used to evaluate the feasibility of using a regulated antisense RNA interference approach to determine antibiotic mode of action. Antisense isogenic strains expressing antisense RNA to fabI were created using a tetracycline-regulated vector in Staphylococcus aureus. We demonstrated that down-regulation of FabI expression by induction of fabI antisense RNA induces a conditional lethal phenotype. In contrast, partial down-regulation gives a viable cell with a significant increase in sensitivity to FabI-specific inhibitors (i.e., a sensitized phenotype). More importantly, the mode of action for novel FabI inhibitors has been confirmed using this genetic approach in whole cell assay. These results indicate that controlled antisense technology provides a robust tool for defining and tracking the mode of action of novel antibacterial agents. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved.
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