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Staphylococcus aureus TargetArray: comprehensive differential essential gene expression as a mechanistic tool to profile antibacterials.
Antimicrob Agents Chemother ; 54(9): 3659-70, 2010 Sep.
Article in En | MEDLINE | ID: mdl-20547796
ABSTRACT
The widespread emergence of antibiotic-resistant bacteria and a lack of new pharmaceutical development have catalyzed a need for new and innovative approaches for antibiotic drug discovery. One bottleneck in antibiotic discovery is the lack of a rapid and comprehensive method to identify compound mode of action (MOA). Since a hallmark of antibiotic action is as an inhibitor of essential cellular targets and processes, we identify a set of 308 essential genes in the clinically important pathogen Staphylococcus aureus. A total of 446 strains differentially expressing these genes were constructed in a comprehensive platform of sensitized and resistant strains. A subset of strains allows either target underexpression or target overexpression by heterologous promoter replacements with a suite of tetracycline-regulatable promoters. A further subset of 236 antisense RNA-expressing clones allows knockdown expression of cognate targets. Knockdown expression confers selective antibiotic hypersensitivity, while target overexpression confers resistance. The antisense strains were configured into a TargetArray in which pools of sensitized strains were challenged in fitness tests. A rapid detection method measures strain responses toward antibiotics. The TargetArray antibiotic fitness test results show mechanistically informative biological fingerprints that allow MOA elucidation.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Staphylococcus aureus / Gene Expression Regulation, Bacterial / Genes, Essential / Anti-Bacterial Agents Language: En Journal: Antimicrob Agents Chemother Year: 2010 Document type: Article Affiliation country: Estados Unidos

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Staphylococcus aureus / Gene Expression Regulation, Bacterial / Genes, Essential / Anti-Bacterial Agents Language: En Journal: Antimicrob Agents Chemother Year: 2010 Document type: Article Affiliation country: Estados Unidos
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