{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:16:17Z","timestamp":1785406577549,"version":"3.56.0"},"posted":{"date-parts":[[2026,1,22]]},"group-title":"Microbiology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["AI158706"],"award-info":[{"award-number":["AI158706"]}],"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,22]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                  and pathogenic nontuberculous mycobacteria pose a growing challenge to human health, and new antibiotics that target new pathways with novel mechanisms of action are urgently needed. Acylaminooxadiazole derivatives have previously been shown to inhibit the\n                  <jats:italic>trans-<\/jats:italic>\n                  translation ribosome rescue pathway and kill\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  . Here, we show that modifications to the acylaminooxadiazole scaffold can improve potency and tune mycobacterial species specificity, resulting in molecules that kill\n                  <jats:italic>M. avium<\/jats:italic>\n                  ,\n                  <jats:italic>M. abscessus<\/jats:italic>\n                  , and\n                  <jats:italic>M. tuberculosis<\/jats:italic>\n                  clinical isolates. Free iron was previously shown to antagonize antibacterial activity and decrease the inhibition of\n                  <jats:italic>trans<\/jats:italic>\n                  -translation by acylaminooxadiazoles, but we found that biologically relevant iron sources such as hemin and transferrin do not affect activity. Mutants depleted for tmRNA and mutants defective in siderophore-mediated iron utilization are both hypersusceptible to acylaminooxadiazole-based\n                  <jats:italic>trans-<\/jats:italic>\n                  translation inhibitors, indicating a dual mechanism of action involving both direct inhibition of\n                  <jats:italic>trans-<\/jats:italic>\n                  translation and metal starvation. These findings establish acylaminooxadiazoles as dual-mechanism antimycobacterial agents that couple inhibition of\n                  <jats:italic>trans<\/jats:italic>\n                  -translation with disruption of iron homeostasis.\n                <\/jats:p>","DOI":"10.64898\/2026.01.22.701086","type":"posted-content","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T02:20:23Z","timestamp":1769134823000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>trans<\/i>\n                  -Translation inhibitors that kill\n                  <i>M. tuberculosis<\/i>\n                  and pathogenic Non-tuberculous Mycobacteria have a dual mechanism of action"],"prefix":"10.64898","author":[{"given":"Akanksha","family":"Varshney","sequence":"first","affiliation":[{"name":"Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyi","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gebremichal","family":"Gebretsadik","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendran","family":"G-Dayanandan","sequence":"additional","affiliation":[{"name":"Microbiotix, Inc., Worcester, MA 01605 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terry L.","family":"Bowlin","sequence":"additional","affiliation":[{"name":"Microbiotix, Inc., Worcester, MA 01605 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle M.","family":"Butler","sequence":"additional","affiliation":[{"name":"Microbiotix, Inc., Worcester, MA 01605 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony D.","family":"Baughn","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN 55455 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth C.","family":"Keiler","sequence":"additional","affiliation":[{"name":"Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712 USA"},{"name":"LaMontagne Center for Infectious Diseases, University of Texas at Austin, Austin, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026020608561326000_2026.01.22.701086v1.1","unstructured":"World Health Organization. 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