title: Novel DNA gyrase inhibitors: microbiological characterisation of pyrrolamides.
abstract: Pyrrolamides are a novel class of antibacterial agents that target DNA gyrase, resulting in inhibition of DNA synthesis and bacterial cell death. In these studies, advanced compounds were shown to have potent in vitro activity against selected Gram-positive and Gram-negative pathogens, including meticillin-resistant Staphylococcus aureus, meticillin- and quinolone-resistant S. aureus, vancomycin-resistant enterococci, penicillin-resistant Streptococcus pneumoniae and β-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. Representatives of the class were demonstrated to be bactericidal, with frequencies of spontaneous resistance ≤1×10(-7) when plated at concentrations equivalent to their minimum inhibitory concentration. Mode of action studies suggested that the activity of these compounds is due to inhibition of the GyrB subunit of DNA gyrase in key pathogens. The antibacterial activity, spectrum and mode of action of these compounds underscore the promise of the pyrrolamide series as attractive candidates for the treatment of several clinical indications, including respiratory and soft tissue infections.
authors.affiliation: AstraZeneca R&D, Infection iMED, 35 Gatehouse Drive, Waltham, MA 02451, USA. Maria.Nickelsen@astrazeneca.com
authors.forename: Maria
authors.initials: M
authors.lastname: Uria-Nickelsen
authors.forename: April
authors.initials: A
authors.lastname: Blodgett
authors.forename: Heather
authors.initials: H
authors.lastname: Kamp
authors.forename: Ann
authors.initials: A
authors.lastname: Eakin
authors.forename: Brian
authors.initials: B
authors.lastname: Sherer
authors.forename: Oluyinka
authors.initials: O
authors.lastname: Green
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D011758:Pyrroles / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors
chemical_list: D000577:Amides; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D011758:Pyrroles; D059005:Topoisomerase II Inhibitors