{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:27:17Z","timestamp":1785803237121,"version":"3.56.0"},"reference-count":30,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["ASM Case Rep"],"published-print":{"date-parts":[[2026,3,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:sec>\n                      <jats:title>Background<\/jats:title>\n                      <jats:p>Bedaquiline (BDQ) has transformed the management of multidrug-resistant (MDR) and rifampin-resistant tuberculosis (TB). Unfortunately, the expanded use of BDQ in these regimens has been accompanied by resistance, which is steadily increasing in certain regions of the world. Nonetheless, our understanding of the mechanisms behind BDQ resistance remains poor, limiting the utility of more rapid molecular or genomic-based diagnostics for the detection of BDQ-resistant isolates.<\/jats:p>\n                    <\/jats:sec>\n                    <jats:sec>\n                      <jats:title>Case Summary<\/jats:title>\n                      <jats:p>\n                        We describe an unusual case of a rapid, 2-year evolution of a fully susceptible\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                        strain to extensively drug-resistant TB in a 44-year-old Canadian-born woman with Crohn\u2019s disease. Comparative whole-genome sequencing captured the progressive development of resistance mutations and identified a novel loss-of-function mutation (Glu-177-STOP) in the\n                        <jats:italic toggle=\"yes\">M. tuberculosis pepQ<\/jats:italic>\n                        gene that was associated with treatment failure while on BDQ and phenotypic BDQ\/clofazimine (CFZ) cross-resistance. Therapeutic drug monitoring while on MDR therapy (daily ethambutol, pyrazinamide, linezolid, CFZ, and intravenous amikacin) detected low serum levels of CFZ, which was not addressed prior to the addition of BDQ to her 5-drug regimen and may have selected for BDQ\/CFZ cross-resistance.\n                      <\/jats:p>\n                    <\/jats:sec>\n                    <jats:sec>\n                      <jats:title>Conclusion<\/jats:title>\n                      <jats:p>\n                        This case contributes to the limited clinical data implicating\n                        <jats:italic toggle=\"yes\">pepQ<\/jats:italic>\n                        in BDQ\/CFZ cross-resistance and describes a novel loss-of-function mutation associated with resistance. As our understanding of genotypic BDQ resistance remains elementary, when novel drug mutations arise, practitioners should consider their significance in the context of phenotypic drug susceptibility test results and the patient\u2019s clinical response.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/asmcr.00126-25","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:00:22Z","timestamp":1762956022000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":2,"title":["Acquisition of bedaquiline and clofazimine resistance in association with a novel loss-of-function mutation in the\n                    <i>pepQ<\/i>\n                    gene during treatment of multidrug-resistant tuberculosis"],"prefix":"10.1128","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6717-8856","authenticated-orcid":true,"given":"Melissa","family":"Richard-Greenblatt","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/025z8ah66","id-type":"ROR","asserted-by":"publisher"}],"name":"Public Health Ontario","place":["Toronto, Canada"]},{"id":[{"id":"https:\/\/ror.org\/00zn2c847","id-type":"ROR","asserted-by":"publisher"}],"name":"Hospital for Sick Children","place":["Toronto, Canada"]},{"id":[{"id":"https:\/\/ror.org\/03dbr7087","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto","place":["Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1279-1738","authenticated-orcid":true,"given":"Ruchika","family":"Bagga","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03dbr7087","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Laboratory Medicine and Pathobiology, University of Toronto","place":["Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Duncan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/025z8ah66","id-type":"ROR","asserted-by":"publisher"}],"name":"Public Health Ontario","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime J.","family":"Billick","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03dbr7087","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Infectious Diseases, University of Toronto","place":["Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Howard","family":"Song","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042xt5161","id-type":"ROR","asserted-by":"publisher"}],"name":"University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha F.","family":"Sabur","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042xt5161","id-type":"ROR","asserted-by":"publisher"}],"name":"University Health Network","place":["Toronto, Canada"]},{"id":[{"id":"https:\/\/ror.org\/03dbr7087","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Respirology, University of Toronto","place":["Toronto, Canada"]},{"id":[{"id":"https:\/\/ror.org\/008te2062","id-type":"ROR","asserted-by":"publisher"}],"name":"Unity Health\u2014St. Michael\u2019s Hospital","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Escuyer","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04hf5kq57","id-type":"ROR","asserted-by":"publisher"}],"name":"Wadsworth Centre, New York State Department of Health","place":["Albany, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Lam","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/025z8ah66","id-type":"ROR","asserted-by":"publisher"}],"name":"Public Health Ontario","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-6368","authenticated-orcid":false,"given":"Sarah K.","family":"Brode","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042xt5161","id-type":"ROR","asserted-by":"publisher"}],"name":"University Health Network","place":["Toronto, Canada"]},{"id":[{"id":"https:\/\/ror.org\/03dbr7087","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Respirology, University of Toronto","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"WHO treatment guidelines for drug-resistant tuberculosis: 2016 update","author":"World Health Organization","year":"2016","unstructured":"World Health Organization. 2016. 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