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As such,\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    is clinically resistant to the entire regimen of front-line\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>tuberculosis<\/jats:italic>\n                    drugs, and treatment with antibiotics that do inhibit\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    in the lab results in cure rates of 50% or less. Here, we identified epetraborole (EPT) from the MMV pandemic response box as an inhibitor against the essential protein leucyl-tRNA synthetase (LeuRS) in\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    . EPT protected zebrafish from lethal\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    infection and did not induce self-resistance nor against clarithromycin. Contrary to most antimycobacterials, the whole-cell activity of EPT was greater against\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    than\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>tuberculosis<\/jats:italic>\n                    , but crystallographic and equilibrium binding data showed that EPT binds LeuRS\n                    <jats:sub>Mabs<\/jats:sub>\n                    and LeuRS\n                    <jats:sub>Mtb<\/jats:sub>\n                    with similar residues and dissociation constants. Since EPT-resistant\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    mutants lost LeuRS editing activity, these mutants became susceptible to misaminoacylation with leucine mimics like the non-proteinogenic amino acid norvaline. Proteomic analysis revealed that when\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    LeuRS mutants were fed norvaline, leucine residues in proteins were replaced by norvaline, inducing the unfolded protein response with temporal changes in expression of GroEL chaperonins and Clp proteases. This supports our\n                    <jats:italic>in vitro<\/jats:italic>\n                    data that supplementation of media with norvaline reduced the emergence of EPT mutants in both\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    and\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>tuberculosis<\/jats:italic>\n                    . Furthermore, the combination of EPT and norvaline had improved\n                    <jats:italic>in vivo<\/jats:italic>\n                    efficacy compared to EPT in a murine model of\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    infection. Our results emphasize the effectiveness of EPT against the clinically relevant cystic fibrosis pathogen\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    , and these findings also suggest norvaline adjunct therapy with EPT could be beneficial for\n                    <jats:italic>M<\/jats:italic>\n                    .\n                    <jats:italic>abscessus<\/jats:italic>\n                    and other mycobacterial infections like tuberculosis.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1009965","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T22:04:20Z","timestamp":1634076260000},"page":"e1009965","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":43,"title":["Efficacy of epetraborole against Mycobacterium abscessus is increased with norvaline"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8864-8949","authenticated-orcid":true,"given":"Jaryd R.","family":"Sullivan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4777-0497","authenticated-orcid":true,"given":"Andr\u00e9anne","family":"Lupien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8420-3320","authenticated-orcid":true,"given":"Elias","family":"Kalthoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0189-3504","authenticated-orcid":true,"given":"Claire","family":"Hamela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorne","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim A.","family":"Munro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8061-0436","authenticated-orcid":true,"given":"T. Martin","family":"Schmeing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6604-4458","authenticated-orcid":true,"given":"Laurent","family":"Kremer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0402-4467","authenticated-orcid":true,"given":"Marcel A.","family":"Behr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,12]]},"reference":[{"key":"ppat.1009965.ref001","article-title":"Non-tuberculous mycobacteria and the rise of Mycobacterium abscessus","author":"MD Johansen","year":"2020","journal-title":"Nat Rev Microbiol"},{"key":"ppat.1009965.ref002","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1164\/rccm.200604-571ST","article-title":"An official ATS\/IDSA statement: Diagnosis, treatment, and 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