| Literature DB >> 19716474 |
Joann Huber1, Robert G K Donald, Sang Ho Lee, Lisa Wang Jarantow, Michael J Salvatore, Xin Meng, Ronald Painter, Russell H Onishi, James Occi, Karen Dorso, Katherine Young, Young Whan Park, Stephen Skwish, Michael J Szymonifka, Tim S Waddell, Lynn Miesel, John W Phillips, Terry Roemer.
Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a major nosocomial and community-acquired pathogen for which few existing antibiotics are efficacious. Here we describe two structurally related synthetic compounds that potentiate beta-lactam activity against MRSA. Genetic studies indicate that these agents target SAV1754 based on the following observations: (i) it has a unique chemical hypersensitivity profile, (ii) overexpression or point mutations are sufficient to confer resistance, and (iii) genetic inactivation phenocopies the potentiating effect of these agents in combination with beta-lactams. Further, we demonstrate these agents inhibit peptidoglycan synthesis. Because SAV1754 is essential for growth and structurally related to the recently reported peptidoglycan flippase of Escherichia coli, we speculate it performs an analogous function in S. aureus. These results suggest that SAV1754 inhibitors might possess therapeutic potential alone, or in combination with beta-lactams to restore MRSA efficacy.Entities:
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Year: 2009 PMID： 19716474 DOI： 10.1016/j.chembiol.2009.05.012
Source DB: PubMed Journal: Chem Biol ISSN： 1074-5521