Chemical Genetic Identification of Peptidoglycan Inhibitors Potentiating Carbapenem Activity against Methicillin-Resistant Staphylococcus aureus

• Published in: Chemistry & biology Vol. 16; no. 8; pp. 837 - 848
• Main Authors: Huber, Joann, Donald, Robert G.K., Lee, Sang Ho, Jarantow, Lisa Wang, Salvatore, Michael J., Meng, Xin, Painter, Ronald, Onishi, Russell H., Occi, James, Dorso, Karen, Young, Katherine, Park, Young Whan, Skwish, Stephen, Szymonifka, Michael J., Waddell, Tim S., Miesel, Lynn, Phillips, John W., Roemer, Terry
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 28.08.2009
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Carbapenems - chemistry; Carbapenems - pharmacology; CHEMBIO; Drug Synergism; Indoles - chemistry; Indoles - pharmacology; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - genetics; MICROBIO; Peptidoglycan - chemistry; Peptidoglycan - metabolism; Piperidines - chemistry; Piperidines - pharmacology; RNA Interference; RNA, Antisense - metabolism; CHEMBIO; MICROBIO
• ISSN: 1074-5521; 1879-1301
• DOI: 10.1016/j.chembiol.2009.05.012

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 β-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 β-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 β-lactams to restore MRSA efficacy.