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<jats:title>ABSTRACT</jats:title> <jats:p> 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 <jats:italic>in vitro</jats:italic> properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of <jats:named-content content-type="genus-species">Escherichia coli</jats:named-content> 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 <jats:named-content content-type="genus-species">Mycobacterium tuberculosis</jats:named-content> . No cross-resistance with fluoroquinolone-resistant <jats:named-content content-type="genus-species">Staphylococcus aureus</jats:named-content> and <jats:named-content content-type="genus-species">E. coli</jats:named-content> isolates was observed. Measured MIC <jats:sub>90</jats:sub> values were 4 and 8 μg/ml against a panel of contemporary multidrug-resistant isolates of <jats:named-content content-type="genus-species">Acinetobacter baumannii</jats:named-content> and <jats:named-content content-type="genus-species">E. coli</jats:named-content> , 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 &lt;10 <jats:sup>−8</jats:sup> against <jats:named-content content-type="genus-species">E. coli</jats:named-content> and <jats:named-content content-type="genus-species">A. baumannii</jats:named-content> at concentrations equivalent to 4-fold the MIC. Compound-resistant <jats:named-content content-type="genus-species">E. coli</jats:named-content> 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 <jats:italic>in vitro</jats:italic> 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 <jats:sub>50</jats:sub> ], &gt;100 μM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable <jats:italic>in vitro</jats:italic> safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents. </jats:p>

Original publication

DOI

10.1128/aac.02100-16

Type

Journal article

Journal

Antimicrobial Agents and Chemotherapy

Publisher

American Society for Microbiology

Publication Date

05/2017

Volume

61