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

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.

01 Mar 2004·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Interactions between Penicillin-Binding Proteins (PBPs) and Two Novel Classes of PBP Inhibitors, Arylalkylidene Rhodanines and Arylalkylidene Iminothiazolidin-4-ones

Q2 · MEDICINE

Article

Author: White, Ronald E. ; Lu, Wei-Ping ; Chen, Zhouliang ; Demuth, Thomas P. ; Frère, Jean-Marie ; Zervosen, Astrid

ABSTRACT Several non-β-lactam compounds were active against various gram-positive and gram-negative bacterial strains. The MICs of arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-ones were lower than those of ampicillin and cefotaxime for methicillin-resistant Staphylococcus aureus MI339 and vancomycin-resistant Enterococcus faecium EF12. Several compounds were found to inhibit the cell wall synthesis of S. aureus and the last two steps of peptidoglycan biosynthesis catalyzed by ether-treated cells of Escherichia coli or cell wall membrane preparations of Bacillus megaterium . The effects of the arylalkylidene rhodanines and arylalkylidene iminothiazolidin-4-one derivatives on E. coli PBP 3 and PBP 5, Streptococcus pneumoniae PBP 2xS (PBP 2x from a penicillin-sensitive strain) and PBP 2xR (PBP 2x from a penicillin-resistant strain), low-affinity PBP 2a of S. aureus , and the Actinomadura sp. strain R39 and Streptomyces sp. strain R61 dd -peptidases were studied. Some of the compounds exhibited inhibitory activities in the 10 to 100 μM concentration range. The inhibition of PBP 2xS by several of them appeared to be noncompetitive. The dissociation constant for the best inhibitor ( Ki = 10 μM) was not influenced by the presence of the substrate.

01 Jan 2003·Annual Reports in Medicinal Chemistry

Chapter 17. Progress in antifungal drug discovery

Author: Fabrey, Robyn ; Roemer, Terry ; Anderson, Mark B.

A review discusses a number of emerging antifungal compounds and recent advances in antifungal agents of a known mechanism of action.

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