Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria

Charrier, Cédric and Salisbury, Anne-Marie and Savage, Victoria J and Duffy, Thomas and Moyo, Emmanuel and Chaffer-Malam, Nathan and Ooi, Nicola and Newman, Rebecca and Cheung, Jonathan and Metzger, Richard and McGarry, David and Pichowicz, Mark and Sigerson, Ralph and Cooper, Ian R and Nelson, Gary and Butler, Hayley S and Craighead, Mark and Ratcliffe, Andrew J and Best, Stuart A and Stokes, Neil R (2017) Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria. Antimicrobial Agents and Chemotherapy. ISSN 0066-4804

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    Abstract

    The Novel Bacterial Topoisomerase Inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that do not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecules. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms, and Mycobacterium tuberculosis No cross-resistance with quinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC90 values were 4 and 8 μg/mL against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies-of-resistance typically <10(-8) against E. coli and A. baumannii at concentrations equivalent to four-fold the MIC. Compound-resistant Ecoli mutants isolated following serial passage were characterised by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminary in vitro safety data indicate that the series shows a promising therapeutic index and potential for low hERG inhibition (IC50 >100 μM). In summary, the compounds' distinct mechanism-of-action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.