{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:35:15Z","timestamp":1785890115453,"version":"3.56.0"},"reference-count":42,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2017,5,1]],"date-time":"2017-05-01T00:00:00Z","timestamp":1493596800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            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\n            <jats:italic>in vitro<\/jats:italic>\n            properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of\n            <jats:named-content content-type=\"genus-species\">Escherichia coli<\/jats:named-content>\n            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\n            <jats:named-content content-type=\"genus-species\">Mycobacterium tuberculosis<\/jats:named-content>\n            . No cross-resistance with fluoroquinolone-resistant\n            <jats:named-content content-type=\"genus-species\">Staphylococcus aureus<\/jats:named-content>\n            and\n            <jats:named-content content-type=\"genus-species\">E. coli<\/jats:named-content>\n            isolates was observed. Measured MIC\n            <jats:sub>90<\/jats:sub>\n            values were 4 and 8 \u03bcg\/ml against a panel of contemporary multidrug-resistant isolates of\n            <jats:named-content content-type=\"genus-species\">Acinetobacter baumannii<\/jats:named-content>\n            and\n            <jats:named-content content-type=\"genus-species\">E. coli<\/jats:named-content>\n            , 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\n            <jats:sup>\u22128<\/jats:sup>\n            against\n            <jats:named-content content-type=\"genus-species\">E. coli<\/jats:named-content>\n            and\n            <jats:named-content content-type=\"genus-species\">A. baumannii<\/jats:named-content>\n            at concentrations equivalent to 4-fold the MIC. Compound-resistant\n            <jats:named-content content-type=\"genus-species\">E. coli<\/jats:named-content>\n            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\n            <jats:italic>in vitro<\/jats:italic>\n            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\n            <jats:sub>50<\/jats:sub>\n            ], &gt;100 \u03bcM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable\n            <jats:italic>in vitro<\/jats:italic>\n            safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.\n          <\/jats:p>","DOI":"10.1128\/aac.02100-16","type":"journal-article","created":{"date-parts":[[2017,2,22]],"date-time":"2017-02-22T01:30:22Z","timestamp":1487727022000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":42,"title":["Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria"],"prefix":"10.1128","volume":"61","author":[{"given":"C\u00e9dric","family":"Charrier","sequence":"first","affiliation":[{"name":"Redx Pharma, Alderley Park, Cheshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Salisbury","sequence":"additional","affiliation":[{"name":"Redx Pharma, Alderley Park, Cheshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria J.","family":"Savage","sequence":"additional","affiliation":[{"name":"Redx Pharma, Alderley Park, Cheshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Duffy","sequence":"additional","affiliation":[{"name":"Redx Pharma, Alderley Park, Cheshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Moyo","sequence":"additional","affiliation":[{"name":"Redx Pharma, Alderley Park, Cheshire, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Chaffer-Malam","sequence":"additional","affiliation":[{"name":"Redx Pharma, Alderley Park, Cheshire, United 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