Murgocil is a Highly Bioactive Staphylococcal-Specific Inhibitor of the Peptidoglycan Glycosyltransferase Enzyme MurG

Rita Sobral Abranches, Mariana Luisa Pinho

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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 'druggable' targets. Here, we describe a beta-lactam potentiation screen to identify small molecules that augment the activity of beta-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 beta-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 beta-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.
Original languageUnknown
Pages (from-to)2442-2451
JournalACS Chemical Biology
Volume8
Issue number11
DOIs
Publication statusPublished - 1 Jan 2013

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