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

Charrier, C. et al. (2017) Novel bacterial topoisomerase inhibitors with potent broad-spectrum activity against drug-resistant bacteria. Antimicrobial Agents and Chemotherapy, 61(5), e02100-16. (doi: 10.1128/AAC.02100-16) (PMID:28223393)

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 E. coli 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sigerson, Mr Ralph
• Authors: Charrier, C., Salisbury, A.-M., Savage, V. J., Duffy, T., Moyo, E., Chaffer-Malam, N., Ooi, N., Newman, R., Cheung, J., Metzger, R., McGarry, D., Pichowicz, M., Sigerson, R., Cooper, I. R., Nelson, G., Butler, H. S., Craighead, M., Ratcliffe, A. J., Best, S. A., and Stokes, N. R.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: Antimicrobial Agents and Chemotherapy
• Publisher: American Society for Microbiology
• ISSN: 0066-4804
• ISSN (Online): 1098-6596
• Published Online: 21 February 2017
• Copyright Holders: Copyright © 2017 American Society for Microbiology
• First Published: First published in Antimicrobial Agents and Chemotherapy 61(5): e02100-16
• Publisher Policy: Reproduced in accordance with the publisher copyright policy