title: Murgocil is a highly bioactive staphylococcal-specific inhibitor of the peptidoglycan glycosyltransferase enzyme MurG.
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 β-lactam potentiation screen to identify small molecules that augment the activity of β-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 β-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 β-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.
authors: Infectious Disease Research, Merck Research Laboratories , Kenilworth, New Jersey 07033, United States.
authors: Paul A
authors: PA
authors: Mann
authors: Anna
authors: A
authors: Müller
authors: Li
authors: L
authors: Xiao
authors: Pedro M
authors: PM
authors: Pereira
authors: Christine
authors: C
authors: Yang
authors: Sang
authors: S
authors: Ho Lee
authors: Hao
authors: H
authors: Wang
authors: Joanna
authors: J
authors: Trzeciak
authors: Jonathan
authors: J
authors: Schneeweis
authors: Margarida Moreira
authors: MM
authors: Dos Santos
authors: Nicholas
authors: N
authors: Murgolo
authors: Xinwei
authors: X
authors: She
authors: Charles
authors: C
authors: Gill
authors: Carl J
authors: CJ
authors: Balibar
authors: Marc
authors: M
authors: Labroli
authors: Jing
authors: J
authors: Su
authors: Amy
authors: A
authors: Flattery
authors: Brad
authors: B
authors: Sherborne
authors: Richard
authors: R
authors: Maier
authors: Christopher M
authors: CM
authors: Tan
authors: Todd
authors: T
authors: Black
authors: Kamil
authors: K
authors: Onder
authors: Stacia
authors: S
authors: Kargman
authors: Frederick J
authors: FJ
authors: Monsma
authors: Mariana G
authors: MG
authors: Pinho
authors: Tanja
authors: T
authors: Schneider
authors: Terry
authors: T
authors: Roemer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors*; D046928:Peptidoglycan Glycosyltransferase / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D013261:Sterols / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D013261:Sterols; C000595254:murgocil; D017351:N-Acetylglucosaminyltransferases; D046928:Peptidoglycan Glycosyltransferase; C064057:UDP-N-acetylglucosamine-N-acetylmuramyl-(pentapeptide)pyrophosphoryl-undecaprenol N-acetylglucosamine transferase