Highly sensitive target-based whole-cell antibacterial discovery strategy by antisense RNA silencing.
Examples of drug-resistant bacteria are increasing while the discovery of new antibiotics with new mechanisms of action has been essentially nonexistent. The antisense-based sensitization of bacterial targets in Staphylococcus aureus is one of the new approaches that provides increased sensitivity for the detection of target-specific antibiotics and whole-cell screening assays based on differential sensitivity of target-depleted strains. The screening of natural product extracts using this type of assay designed for condensing enzyme (FabH/FabF) targets of the fatty acid biosynthesis pathway led to the discovery of a number of target-specific inhibitors including the novel antibiotic platensimycin, which has displayed activity against various drug-resistant bacteria. The antisense-based discovery strategy, rationale and design of screening assays, and the application of such assays for screening of natural product extracts and the discovery of fatty acid condensing enzyme inhibitors are reviewed in this article.
Singh
Sheo B
SB
Merck Research Laboratories, RY80Y-350, 126 E Lincoln Avenue, Rahway, NJ 07065, USA. sheo_singh@merck.com
Phillips
John W
JW
Wang
Jun
J
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D015195:Drug Design; D020868:Gene Silencing / Q000187:drug effects*; D006801:Humans; D012313:RNA / Q000096:biosynthesis; D016372:RNA, Antisense / Q000096:biosynthesis / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D016372:RNA, Antisense; D012313:RNA