title: Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin.
abstract: Terreic acid is a metabolite with antibiotic properties produced by the fungus Aspergillus terreus, but its cellular target remains unknown. We recently reported that terreic acid inactivates the bacterial cell wall biosynthetic enzyme MurA in vitro by covalent reaction with residue Cys115 in a similar manner as the MurA-specific antibiotic fosfomycin. To address if terreic acid also targets MurA in vivo, we conducted antibacterial studies using selected E. coli strains in parallel with fosfomycin. While overexpression of MurA conferred resistance to fosfomycin, it did not protect cells treated with terreic acid. Furthermore, flow cytometry revealed that the antibiotic action of terreic acid appears to be primarily bacteriostatic, as opposed to the bactericidal action observed for fosfomycin. Combined, the data suggest that MurA is not the molecular target of terreic acid and that the antibiotic activity of terreic acid proceeds through a different mechanism of action. The methodology applied here provides a reliable and convenient tool to rapidly assess the potential of newly discovered in vitro inhibitors to target residue Cys115 of MurA in the cell.
authors.affiliation: Drug Discovery Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Sanne H
authors.initials: SH
authors.lastname: Olesen
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Ingles
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ernst
authors.initials: E
authors.lastname: Schönbrunn
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001230:Aspergillus; D049109:Cell Proliferation / Q000187:drug effects; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D005578:Fosfomycin / Q000494:pharmacology*; D009154:Mutation; D011809:Quinones / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D011809:Quinones; D005578:Fosfomycin; D019883:Alkyl and Aryl Transferases; C022566:UDP-N-acetylglucosamine 1-carboxyvinyltransferase; C009400:terreic acid
keywords: Antibiotics; Drug discovery; Flow cytometry; Natural products; Terreic acid