Rethinking ramoplanin: the role of substrate binding in inhibition of peptidoglycan biosynthesis.
Ramoplanin is a cyclicdepsipeptide antibiotic that inhibits peptidoglycan biosynthesis. It was proposed in 1990 to block the MurG step of peptidoglycan synthesis by binding to the substrate of MurG, Lipid I. The proposed mechanism of MurG inhibition has become widely accepted even though it was never directly tested. In this paper, we disprove the accepted mechanism for how ramoplanin functions, and we present an alternative mechanism. This work has implications for the design of ramoplanin derivatives and may influence how other proposed substrate binding antibiotics are studied.
Helm
Jeremiah S
JS
Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
Chen
Lan
L
Walker
Suzanne
S
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001425:Bacterial Outer Membrane Proteins; D047630:Depsipeptides; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D009005:Monosaccharides / Q000378:metabolism; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D010457:Peptidoglycan / Q000096:biosynthesis*
D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D009005:Monosaccharides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010457:Peptidoglycan; C438940:lipid I; C041438:ramoplanin; D017351:N-Acetylglucosaminyltransferases; C064057:UDP-N-acetylglucosamine-N-acetylmuramyl-(pentapeptide)pyrophosphoryl-undecaprenol N-acetylglucosamine transferase