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Xu, H. Howard; Trawick, John D.; Haselbeck, Robert J.; Forsyth, R. Allyn; Yamamoto, Robert T.; Archer, Rich; Patterson, Joe; Allen, Molly; Froelich, Jamie M.; Taylor, Ian; Nakaji, Danny; Maile, Randy; G. C., Kedar; Pilcher, Marshall; Brown-Driver, Vickie; McCarthy, Melissa; Files, Amy; Robbins, David; King, Paula; Sillaots, Susan; Malone, Cheryl; Zamudio, Carlos S.; Roemer, Terry; Wang, Liangsu; [...]

Staphylococcus aureus TargetArray: Comprehensive Differential Essential Gene Expression as a Mechanistic Tool To Profile Antibacterials

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  • Media type: E-Article
  • Title: Staphylococcus aureus TargetArray: Comprehensive Differential Essential Gene Expression as a Mechanistic Tool To Profile Antibacterials
  • Contributor: Xu, H. Howard; Trawick, John D.; Haselbeck, Robert J.; Forsyth, R. Allyn; Yamamoto, Robert T.; Archer, Rich; Patterson, Joe; Allen, Molly; Froelich, Jamie M.; Taylor, Ian; Nakaji, Danny; Maile, Randy; G. C., Kedar; Pilcher, Marshall; Brown-Driver, Vickie; McCarthy, Melissa; Files, Amy; Robbins, David; King, Paula; Sillaots, Susan; Malone, Cheryl; Zamudio, Carlos S.; Roemer, Terry; Wang, Liangsu; [...]
  • imprint: American Society for Microbiology, 2010
  • Published in: Antimicrobial Agents and Chemotherapy
  • Language: English
  • DOI: 10.1128/aac.00308-10
  • ISSN: 0066-4804; 1098-6596
  • Keywords: Infectious Diseases ; Pharmacology (medical) ; Pharmacology
  • Origination:
  • Footnote:
  • Description: <jats:title>ABSTRACT</jats:title> <jats:p> 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 <jats:italic>Staphylococcus aureus</jats:italic> . 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. </jats:p>
  • Access State: Open Access