title: Chemical, biochemical and microbiological properties of a brominated nitrovinylfuran with broad-spectrum antibacterial activity.
abstract: A di-bromo substituted nitrovinylfuran with reported broad-spectrum antibacterial activity was found to be a potent inhibitor of MurA, a key enzyme in peptidoglycan biosynthesis. Further characterization of the compound was carried out to assess its reactivity towards thiol nucleophiles, its stability and degradation under aqueous conditions, inhibitory potential at other enzymes, and antibacterial and cytotoxic activity. Our results indicate that the nitrovinylfuran derivative is reactive towards cysteine residues in proteins, as demonstrated by the irreversible inhibition of MurA and bacterial methionine aminopeptidase. Experiments with proteins and model thiols indicate that the compound forms covalent adducts with SH groups and induces intermolecular disulfide bonds, with the intermediate formation of a monobromide derivative. The parent molecule as well as most of its breakdown products are potent antibiotics with MIC values below 4 μg/mL and are active against multiresistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). Further development of the bromonitrovinyl scaffold towards antibiotics with clinical relevance, however, requires optimization of the antibiotic-cytotoxic selectivity profile.
authors.affiliation: Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology IPMB, Heidelberg University, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.
authors.forename: Therese
authors.initials: T
authors.lastname: Scholz
authors.forename: Carina L
authors.initials: CL
authors.lastname: Heyl
authors.forename: Dan
authors.initials: D
authors.lastname: Bernardi
authors.forename: Stefan
authors.initials: S
authors.lastname: Zimmermann
authors.forename: Lars
authors.initials: L
authors.lastname: Kattner
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009581:Nitrofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D009581:Nitrofurans