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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




Journal article


Antimicrobial Agents and Chemotherapy


American Society for Microbiology

Publication Date