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To capture these intermediate steps in\n              <jats:italic>Mycobacterium abscessus<\/jats:italic>\n              (Mab), we performed classic mutant selection experiments with moxifloxacin at twofold its minimum inhibitory concentration (MIC) on solid medium. We found that low-level resistance emerged reproducibly as loss-of-function mutations in RshA (MAB_3542c), an anti-sigma factor that negatively regulates activity of SigH, which orchestrates a response to oxidative stress in mycobacteria. Since oxidative stress is generated in response to many antibiotics, we went on to show that deletion of\n              <jats:italic>rshA<\/jats:italic>\n              confers low to moderate resistance\u2014by measure of MIC\u2014to a dozen agents recommended or evaluated for the treatment of Mab pulmonary infections. Interestingly, this moderate resistance was associated with a wide range of drug tolerance, up to 1,000-fold increased survival of a \u0394\n              <jats:italic>rshA<\/jats:italic>\n              Mab mutant upon exposure to several \u03b2-lactams and DNA gyrase inhibitors. Consistent with the putative involvement of the SigH regulon, we showed that addition of the transcription inhibitor rifabutin (RBT) abrogated the high-tolerance phenotype of \u0394\n              <jats:italic>rshA<\/jats:italic>\n              to representatives of the \u03b2-lactam and DNA gyrase inhibitor classes. In a survey of 10,000 whole Mab genome sequences, we identified several loss-of-function mutations in\n              <jats:italic>rshA<\/jats:italic>\n              as well as non-synonymous polymorphisms in two cysteine residues critical for interactions with SigH. Thus, the multidrug multiform resistance phenotype we have uncovered may not only constitute a step toward canonical resistance acquisition during treatment but also contribute directly to treatment failure.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/aac.01051-24","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T13:00:38Z","timestamp":1730206838000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Multidrug tolerance conferred by loss-of-function mutations in anti-sigma factor RshA of\n            <i>Mycobacterium abscessus<\/i>"],"prefix":"10.1128","volume":"68","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4199-2224","authenticated-orcid":false,"given":"Wassihun Wedajo","family":"Aragaw","sequence":"first","affiliation":[{"name":"Center for Discovery and Innovation, Hackensack Meridian Health","place":["Nutley, 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