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 (https://doi.org/10.1128/AAC.02100-16)
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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.
ORCID iDs
Charrier, Cédric, Salisbury, Anne-Marie, Savage, Victoria J, Duffy, Thomas, Moyo, Emmanuel, Chaffer-Malam, Nathan, Ooi, Nicola, Newman, Rebecca, Cheung, Jonathan, Metzger, Richard, McGarry, David ORCID: https://orcid.org/0000-0002-7087-0584, Pichowicz, Mark, Sigerson, Ralph, Cooper, Ian R, Nelson, Gary, Butler, Hayley S, Craighead, Mark, Ratcliffe, Andrew J, Best, Stuart A and Stokes, Neil R;-
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Item type: Article ID code: 60125 Dates: DateEvent21 February 2017Published21 February 2017Published Online27 January 2017AcceptedNotes: Copyright © 2017 American Society for Microbiology. Subjects: Science > Microbiology Department: Faculty of Science > Pure and Applied Chemistry Depositing user: Pure Administrator Date deposited: 10 Mar 2017 09:17 Last modified: 06 Oct 2024 00:29 URI: https://strathprints.strath.ac.uk/id/eprint/60125