Murgocil is a Highly Bioactive Staphylococcal-Specific Inhibitor of the Peptidoglycan Glycosyltransferase Enzyme MurG
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- 作者：Paul A. Mann ; Anna M眉ller ; Li Xiao ; Pedro M. Pereira ; Christine Yang ; Sang Ho Lee ; Hao Wang ; Joanna Trzeciak ; Jonathan Schneeweis ; Margarida Moreira dos Santos ; Nicholas Murgolo ; Xinwei She ; Charles Gill ; Carl J. Balibar ; Marc Labroli ; Jing Su ; Amy Flattery ; Brad Sherborne ; Richard Maier ; Christopher M. Tan ; Todd Black ; Kamil 脰nder ; Stacia Kargman ; Frederick J Monsma ; Jr. ; Mariana G. Pinho ; Tanja Schneider ; Terry Roemer
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：November 15, 2013
- 年：2013
- 卷：8
- 期：11
- 页码：2442-2451
- 全文大小：587K
- 年卷期：v.8,no.11(November 15, 2013)
- ISSN：1554-8937
文摘
Modern medicine is founded on the discovery of penicillin and subsequent small molecules that inhibit bacterial peptidoglycan (PG) and cell wall synthesis. However, the discovery of new chemically and mechanistically distinct classes of PG inhibitors has become exceedingly rare, prompting speculation that intracellular enzymes involved in PG precursor synthesis are not 鈥榙ruggable鈥?targets. Here, we describe a 尾-lactam potentiation screen to identify small molecules that augment the activity of 尾-lactams against methicillin-resistant Staphylococcus aureus (MRSA) and mechanistically characterize a compound resulting from this screen, which we have named murgocil. We provide extensive genetic, biochemical, and structural modeling data demonstrating both in vitro and in whole cells that murgocil specifically inhibits the intracellular membrane-associated glycosyltransferase, MurG, which synthesizes the lipid II PG substrate that penicillin binding proteins (PBPs) polymerize and cross-link into the cell wall. Further, we demonstrate that the chemical synergy and cidality achieved between murgocil and the 尾-lactam imipenem is mediated through MurG dependent localization of PBP2 to the division septum. Collectively, these data validate our approach to rationally identify new target-specific bioactive 尾-lactam potentiation agents and demonstrate that murgocil now serves as a highly selective and potent chemical probe to assist our understanding of PG biosynthesis and cell wall biogenesis across Staphylococcal species.