Please use this identifier to cite or link to this item: http://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/7339
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dc.contributor.authorShee, Somnathen_US
dc.contributor.authorKUMAR, ANAND Ten_US
dc.contributor.authorCHAKRAPANI, HARINATH et al.en_US
dc.date.accessioned2022-08-30T08:49:26Z
dc.date.available2022-08-30T08:49:26Z
dc.date.issued2022-09en_US
dc.identifier.citationAntimicrobial Agents and Chemotherapy, 66(9).en_US
dc.identifier.issn0066-4804en_US
dc.identifier.issn1098-6596en_US
dc.identifier.urihttps://doi.org/10.1128/aac.00592-22en_US
dc.identifier.urihttp://dr.iiserpune.ac.in:8080/xmlui/handle/123456789/7339
dc.description.abstractMoxifloxacin is central to treatment of multidrug-resistant tuberculosis. Effects of moxifloxacin on the Mycobacterium tuberculosis redox state were explored to identify strategies for increasing lethality and reducing the prevalence of extensively resistant tuberculosis. A noninvasive redox biosensor and a reactive oxygen species (ROS)-sensitive dye revealed that moxifloxacin induces oxidative stress correlated with M. tuberculosis death. Moxifloxacin lethality was mitigated by supplementing bacterial cultures with an ROS scavenger (thiourea), an iron chelator (bipyridyl), and, after drug removal, an antioxidant enzyme (catalase). Lethality was also reduced by hypoxia and nutrient starvation. Moxifloxacin increased the expression of genes involved in the oxidative stress response, iron-sulfur cluster biogenesis, and DNA repair. Surprisingly, and in contrast with Escherichia coli studies, moxifloxacin decreased expression of genes involved in respiration, suppressed oxygen consumption, increased the NADH/NAD+ ratio, and increased the labile iron pool in M. tuberculosis. Lowering the NADH/NAD+ ratio in M. tuberculosis revealed that NADH-reductive stress facilitates an iron-mediated ROS surge and moxifloxacin lethality. Treatment with N-acetyl cysteine (NAC) accelerated respiration and ROS production, increased moxifloxacin lethality, and lowered the mutant prevention concentration. Moxifloxacin induced redox stress in M. tuberculosis inside macrophages, and cotreatment with NAC potentiated the antimycobacterial efficacy of moxifloxacin during nutrient starvation, inside macrophages, and in mice, where NAC restricted the emergence of resistance. Thus, NADH-reductive stress contributes to moxifloxacin-mediated killing of M. tuberculosis, and the respiration stimulator (NAC) enhances lethality and suppresses the emergence of drug resistance.en_US
dc.language.isoenen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.subjectAntimycobacterialen_US
dc.subjectROSen_US
dc.subjectOxidative stressen_US
dc.subjectMoxifloxacinen_US
dc.subjectFluoroquinoloneen_US
dc.subjectRespirationen_US
dc.subjectN-acetyl cysteineen_US
dc.subjectRedox biosensoren_US
dc.subjectNadhen_US
dc.subjectReductive stressen_US
dc.subjectResistanceen_US
dc.subject2022-AUG-WEEK5en_US
dc.subjectTOC-AUG-2022en_US
dc.subject2022en_US
dc.titleMoxifloxacin-Mediated Killing of Mycobacterium tuberculosis Involves Respiratory Downshift, Reductive Stress, and Accumulation of Reactive Oxygen Speciesen_US
dc.typeArticleen_US
dc.contributor.departmentDept. of Chemistryen_US
dc.identifier.sourcetitleAntimicrobial Agents and Chemotherapyen_US
dc.publication.originofpublisherForeignen_US
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