{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:53:42Z","timestamp":1785412422897,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,1]]},"group-title":"Microbiology","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["CORLEY23F0"],"award-info":[{"award-number":["CORLEY23F0"]}],"id":[{"id":"https:\/\/ror.org\/00ax59295","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NICK20Y2-SVC"],"award-info":[{"award-number":["NICK20Y2-SVC"]}],"id":[{"id":"https:\/\/ror.org\/00ax59295","id-type":"ROR","asserted-by":"publisher"}]},{"award":["NICK20Y2"],"award-info":[{"award-number":["NICK20Y2"]}],"id":[{"id":"https:\/\/ror.org\/00ax59295","id-type":"ROR","asserted-by":"publisher"}]},{"award":["HISERT19R3"],"award-info":[{"award-number":["HISERT19R3"]}],"id":[{"id":"https:\/\/ror.org\/00ax59295","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01HL167956"],"award-info":[{"award-number":["R01HL167956"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Nontuberculous mycobacteria (NTM) are opportunistic pathogens that cause pulmonary disease (PD) in people with bronchiectasis and other chronic airways diseases. Difficulty treating and eradicating NTM-PD highlights the need for improved understanding of bacterial mechanisms to establish chronic infections. People with the genetic disorder cystic fibrosis (CF) develop bronchiectasis and are the population at highest risk of NTM-PD, caused mainly by\n                  <jats:italic>Mycobacterium avium<\/jats:italic>\n                  or\n                  <jats:italic>Mycobacterium abscessus<\/jats:italic>\n                  (\n                  <jats:italic>Mabsc<\/jats:italic>\n                  ). The majority of people with CF (pwCF) and bronchiectasis develop chronic\n                  <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                  airway infections. We hypothesized that antibiotics used to treat\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  infections could enhance\n                  <jats:italic>Mabsc<\/jats:italic>\n                  persistence in the CF airway. Here we demonstrate that clinically relevant concentrations of tobramycin, which does not kill\n                  <jats:italic>Mabsc<\/jats:italic>\n                  but is frequently administered to pwCF with chronic\n                  <jats:italic>P. aeruginosa<\/jats:italic>\n                  infections, induced\n                  <jats:italic>Mabsc<\/jats:italic>\n                  expression of\n                  <jats:italic>whiB7<\/jats:italic>\n                  , a transcription factor that activates genes associated with resistance to host defenses. Tobramycin promoted\n                  <jats:italic>Mabsc<\/jats:italic>\n                  resistance to killing by hydrogen peroxide (H\n                  <jats:sub>2<\/jats:sub>\n                  O\n                  <jats:sub>2<\/jats:sub>\n                  ) and survival in both human macrophages and mice. Deletion of\n                  <jats:italic>whiB7<\/jats:italic>\n                  increased\n                  <jats:italic>Mabsc<\/jats:italic>\n                  susceptibility to killing by H\n                  <jats:sub>2<\/jats:sub>\n                  O\n                  <jats:sub>2<\/jats:sub>\n                  , decreased ability of\n                  <jats:italic>Mabsc<\/jats:italic>\n                  to persist in macrophages, and disrupted ability of tobramycin to enhance\n                  <jats:italic>Mabsc<\/jats:italic>\n                  survival. Transcriptomic data defining the tobramycin associated WhiB7 regulon revealed differential gene expression of factors that could enhance\n                  <jats:italic>Mabsc<\/jats:italic>\n                  resistance to stress conditions such as those in found in the CF lung. Overall, our data indicate that administration of tobramycin to pwCF may have unexpected off-target effects, enhancing\n                  <jats:italic>Mabsc whiB7<\/jats:italic>\n                  expression and promoting\n                  <jats:italic>Mabsc<\/jats:italic>\n                  persistent infection.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Pulmonary infections caused by\n                    <jats:italic>Mycobacterium abscessus<\/jats:italic>\n                    (\n                    <jats:italic>Mabsc<\/jats:italic>\n                    ) are increasing in prevalence, especially in people with cystic fibrosis (pwCF) and bronchiectasis, and are very challenging to treat. Risk factors that predispose to\n                    <jats:italic>Mabsc<\/jats:italic>\n                    pulmonary infections remain poorly defined. This study demonstrates that tobramycin, an antibiotic commonly used to treat chronic\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    infections in pwCF, promotes\n                    <jats:italic>Mabsc<\/jats:italic>\n                    persistence by inducing\n                    <jats:italic>Mabsc<\/jats:italic>\n                    expression of the transcription factor\n                    <jats:italic>whiB7<\/jats:italic>\n                    . WhiB7 enhances\n                    <jats:italic>Mabsc<\/jats:italic>\n                    resistance to oxidative stress and survival in host macrophages. Transcriptome analysis reveals that tobramycin activates a large WhiB7 dependent regulon linked to stress tolerance and immune evasion.\n                  <\/jats:p>\n                  <jats:p>\n                    These findings highlight a clinically relevant off-target effect of tobramycin that may contribute to\n                    <jats:italic>Mabsc<\/jats:italic>\n                    persistence in polymicrobial infections.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.01.679559","type":"posted-content","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T04:25:13Z","timestamp":1759379113000},"source":"Crossref","is-referenced-by-count":2,"title":["Tobramycin enhances\n                  <i>Mycobacterium abscessus<\/i>\n                  fitness through\n                  <i>whiB7<\/i>\n                  induction"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7734-7331","authenticated-orcid":false,"given":"Jodi M.","family":"Corley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack H.","family":"Congel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey C.","family":"Haist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alma E.","family":"Ochoa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth C.","family":"Malcolm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Janssen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jerry A.","family":"Nick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine B.","family":"Hisert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025100421200791000_2025.10.01.679559v1.1","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/j.ccm.2022.06.010","article-title":"Nontuberculous Mycobacterial Infections in Cystic Fibrosis","volume":"43","year":"2022","journal-title":"Clin. 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