{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T13:45:30Z","timestamp":1790430330198,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004569","name":"Ministerstwo Edukacji i Nauki","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004569","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Fluoroquinolones (FQs) are pharmacological cornerstone agents in global tuberculosis (TB) management, critical for both accelerating drug-sensitive regimens and defining the resistance spectrum of multidrug-resistant TB.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods &amp;amp; Results<\/jats:title>\n                    <jats:p>\n                      To evaluate the therapeutic potential of this class across the mycobacterial spectrum, we conducted a comprehensive phenotypic screening campaign utilizing OTAVA and ECBD pilot-libraries against reference strains of\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      (\n                      <jats:italic>Mtb<\/jats:italic>\n                      ) and\n                      <jats:italic>Mycobacterium abscessus<\/jats:italic>\n                      (\n                      <jats:italic>Mab<\/jats:italic>\n                      ). This initial screen, followed by detailed bactericidal concentration (BC) and cytotoxicity assessments, identified and selected potent FQ derivatives for in-depth characterization. These FQ compounds exhibited exceptionally high potency against\n                      <jats:italic>Mtb<\/jats:italic>\n                      , with several demonstrating robust bactericidal activity at concentrations far below toxic levels to mammalian cells. This activity was retained in clinically relevant, challenging states, as the compounds effectively eliminated\n                      <jats:italic>Mtb<\/jats:italic>\n                      residing within human macrophages and persisted within protective biofilm structures. In stark contrast,\n                      <jats:italic>Mab<\/jats:italic>\n                      displayed marked intrinsic resistance. Most FQ derivatives highly potent against\n                      <jats:italic>Mtb<\/jats:italic>\n                      required significantly higher concentrations for inhibition and bactericidal effect against\n                      <jats:italic>Mab<\/jats:italic>\n                      . For instance, a leading clinical FQ showed substantially diminished activity against\n                      <jats:italic>Mab<\/jats:italic>\n                      compared to\n                      <jats:italic>Mtb<\/jats:italic>\n                      . Analysis of acquired resistance mechanisms demonstrated that both\n                      <jats:italic>Mtb<\/jats:italic>\n                      and\n                      <jats:italic>Mab<\/jats:italic>\n                      primarily rely on similar acquired point mutations in the Quinolone Resistance Determining Regions (QRDRs) of the\n                      <jats:italic>gyrA<\/jats:italic>\n                      and\n                      <jats:italic>gyrB<\/jats:italic>\n                      genes. However, molecular docking indicated a slight but significant reduction in theoretical binding affinity to the\n                      <jats:italic>Mab<\/jats:italic>\n                      gyrase complex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      We hypothesize that the profound differential in intrinsic susceptibility is at least partially driven by non-target factors. This work supports the continued critical role of FQs in\n                      <jats:italic>Mtb<\/jats:italic>\n                      therapy while highlighting the importance of structural modifications that could address hypothesized intrinsic resistance mechanisms in\n                      <jats:italic>Mab<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcimb.2026.1833650","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T04:56:34Z","timestamp":1779944194000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Fluoroquinolones as the linchpin of tuberculosis therapy: contrasting efficacy and resistance profiles in Mycobacterium tuberculosis versus Mycobacterium abscessus"],"prefix":"10.3389","volume":"16","author":[{"given":"Magdalena","family":"Kuzio\u0142a","sequence":"first","affiliation":[{"name":"Institute of Medical Biology, Polish Academy of Sciences","place":["\u0141\u00f3d\u017a, Poland"]},{"name":"The Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"Korycka-Macha\u0142a","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Polish Academy of Sciences","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Zyga\u0142a-Pytlos","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Polish Academy of Sciences","place":["\u0141\u00f3d\u017a, Poland"]},{"name":"The Bio-Med-Chem Doctoral School of the University of Lodz and Lodz Institutes of the Polish Academy of Sciences","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo\u017cena","family":"Dziadek","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, University of \u0141\u00f3d\u017a, Faculty of Biology and Environmental Protection","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malwina","family":"Kawka","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology, University of \u0141\u00f3d\u017a, Faculty of Biology and Environmental Protection","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Pawe\u0142czyk","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Polish Academy of Sciences","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Odolczyk","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences","place":["Warsaw, Poland"]},{"name":"Faculty of Biology, University of Warsaw","place":["Warsaw, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piotr","family":"Zielenkiewicz","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences","place":["Warsaw, Poland"]},{"name":"Faculty of Biology, University of Warsaw","place":["Warsaw, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"S\u0142omka","sequence":"additional","affiliation":[{"name":"Faculty of Biology and Environmental Protection, University of \u0141\u00f3d\u017a, Centre for Digital Biology and Biomedical Science \u2013 Biobank \u0141\u00f3d\u017a","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaros\u0142aw","family":"Dziadek","sequence":"additional","affiliation":[{"name":"Institute of Medical Biology, Polish Academy of Sciences","place":["\u0141\u00f3d\u017a, Poland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00959-2021","article-title":"Is the new WHO definition of extensively drug-resistant tuberculosis easy to apply in practice","volume":"58","author":"Alagna","year":"2021","journal-title":"Eur. 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