Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria.

Autor: Charrier C; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Salisbury AM; Redx Pharma, Alderley Park, Cheshire, United Kingdom am.salisbury@redxpharma.com., Savage VJ; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Duffy T; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Moyo E; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Chaffer-Malam N; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Ooi N; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Newman R; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Cheung J; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Metzger R; Redx Pharma, Alderley Park, Cheshire, United Kingdom., McGarry D; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Pichowicz M; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Sigerson R; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Cooper IR; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Nelson G; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Butler HS; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Craighead M; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Ratcliffe AJ; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Best SA; Redx Pharma, Alderley Park, Cheshire, United Kingdom., Stokes NR; Redx Pharma, Alderley Park, Cheshire, United Kingdom.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2017 Apr 24; Vol. 61 (5). Date of Electronic Publication: 2017 Apr 24 (Print Publication: 2017).
DOI: 10.1128/AAC.02100-16
Abstrakt: The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does 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 molecule. 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 fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC 90 values were 4 and 8 μg/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli , respectively. 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 4-fold the MIC. Compound-resistant E. coli mutants that were isolated following serial passage were characterized 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 human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC 50 ], >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.
(Copyright © 2017 American Society for Microbiology.)
Databáze: MEDLINE
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