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.