Novel DNA gyrase inhibitors: microbiological characterisation of pyrrolamides.

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.

Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents.

DNA gyrase is an essential enzyme in bacteria, and its inhibition results in the disruption of DNA synthesis and, subsequently, cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compounds were identified by a fragment-based lead generation (FBLG) approach using nuclear magnetic resonance (NMR) screening to identify low-molecular-weight compounds that bind to the ATP pocket of DNA gyrase.

Utilization of target-specific, hypersensitive strains of Saccharomyces cerevisiae to determine the mode of action of antifungal compounds.

Target-specific hypersusceptible strains of Saccharomyces cerevisiae were used to screen antifungal compounds. Two novel Erg7p inhibitors were identified, providing proof of principle of the approach taken. However, observed hypersensitivities to antifungals acting via other targets imply that use of this tool to identify the mode of action requires significant deconvolution.

Pyridines and pyrimidines mediating activity against an efflux-negative strain of Candida albicans through putative inhibition of lanosterol demethylase.

The first step in ergosterol biosynthesis in Saccharomyces cerevisiae consists of the condensation of two acetyl coenzyme A (acetyl-CoA) moieties by acetoacetyl-CoA thiolase, encoded by ERG10. The inhibition of the sterol pathway results in feedback activation of ERG10 transcription. A cell-based reporter assay, in which increased ERG10 transcription results in elevated specific beta-galactosidase activity, was used to find novel inhibitors of ergosterol biosynthesis that could serve as chemical starting points for the development of novel antifungal agents.