{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T19:45:22Z","timestamp":1782935122724,"version":"3.54.5"},"reference-count":139,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T00:00:00Z","timestamp":1664409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>With tuberculosis, the emergence of fluoroquinolone resistance erodes the ability of treatment to interrupt the progression of MDR-TB to XDR-TB. One way to reduce the emergence of resistance is to identify heteroresistant infections in which subpopulations of resistant mutants are likely to expand and make the infections fully resistant: treatment modification can be instituted to suppress mutant enrichment. Rapid DNA-based detection methods exploit the finding that fluoroquinolone-resistant substitutions occur largely in a few codons of DNA gyrase. A second approach for restricting the emergence of resistance involves understanding fluoroquinolone lethality through studies of antimicrobial tolerance, a condition in which bacteria fail to be killed even though their growth is blocked by lethal agents. Studies with<jats:italic>Escherichia coli<\/jats:italic>guide work with<jats:italic>Mycobacterium tuberculosis<\/jats:italic>. Lethal action, which is mechanistically distinct from blocking growth, is associated with a surge in respiration and reactive oxygen species (ROS). Mutations in carbohydrate metabolism that attenuate ROS accumulation create pan-tolerance to antimicrobials, disinfectants, and environmental stressors. These observations indicate the existence of a general death pathway with respect to stressors.<jats:italic>M. tuberculosis<\/jats:italic>displays a variation on the death pathway idea, as stress-induced ROS is generated by NADH-mediated reductive stress rather than by respiration. A third approach, which emerges from lethality studies, uses a small molecule, N-acetyl cysteine, to artificially increase respiration and additional ROS accumulation. That enhances moxifloxacin lethality with<jats:italic>M. tuberculosis<\/jats:italic>in culture, during infection of cultured macrophages, and with infection of mice. Addition of ROS stimulators to fluoroquinolone treatment of tuberculosis constitutes a new direction for suppressing the transition of MDR-TB to XDR-TB.<\/jats:p>","DOI":"10.3389\/fcimb.2022.938032","type":"journal-article","created":{"date-parts":[[2022,9,29]],"date-time":"2022-09-29T17:30:25Z","timestamp":1664472625000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Fluoroquinolone heteroresistance, antimicrobial tolerance, and lethality enhancement"],"prefix":"10.3389","volume":"12","author":[{"given":"Amit","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xilin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Drlica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049433","article-title":"Evaluation of genotype MTBDRsl assay to detect drug resistance associated with fluoroquinolones, aminoglycosides and ethambutol on clinical sediments","volume":"7","author":"Ajbani","year":"2012","journal-title":"PloS One"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1021\/bi5000564","article-title":"Mechanism of quinolone action and resistance","volume":"53","author":"Aldred","year":"2014","journal-title":"Biochemistry"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00508","article-title":"Mechanisms of control of Mycobacterium tuberculosis by NK cells: Role of glutathione","volume":"6","author":"Allen","year":"2015","journal-title":"Front. 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