{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:24:15Z","timestamp":1788269055527,"version":"build-2803163510"},"reference-count":32,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001713","name":"European and Developing Countries Clinical Trials Partnership","doi-asserted-by":"publisher","award":["DRIA2014-326"],"award-info":[{"award-number":["DRIA2014-326"]}],"id":[{"id":"10.13039\/501100001713","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005027","name":"Belgisch Ontwikkelingsagentschap","doi-asserted-by":"publisher","award":["911063\/70\/150"],"award-info":[{"award-number":["911063\/70\/150"]}],"id":[{"id":"10.13039\/501100005027","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2026,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      The interpretation of genetic variants\u2019 association (or not) with phenotypic resistance to newly introduced and repurposed antituberculosis drugs remains challenging, as many mutations detected by whole-genome sequencing (WGS) are classified as of uncertain significance (group 3) or not associated with resistance-interim (group 4) by the World Health Organization (WHO) mutation catalog v2. We evaluated the phenotypic impact of such variants on minimum inhibitory concentrations (MICs) for bedaquiline (BDQ), clofazimine (CFZ), delamanid (DLM), and pretomanid (PA) in\n                      <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                      complex isolates from the multi-country DIAMA cohort in sub-Saharan Africa (SSA), which recruited RR\/RS-TB patients na\u00efve to these drugs. Among 1,475 isolates with available WGS data, 163 variants met eligibility criteria; due to viable strain unavailability, 89 isolates carrying 29 unique BDQ\/CFZ-related and 60 unique DLM\/PA-related variants were tested for MIC determination using broth microdilution. Additional structural modeling was performed to explore potential effects of amino-acid substitutions on protein stability. Among BDQ\/CFZ-related variants, MICs above the critical concentrations (CCs) were consistently associated with\n                      <jats:italic toggle=\"yes\">mmpR5<\/jats:italic>\n                      variants, whereas variants in\n                      <jats:italic toggle=\"yes\">atpE<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">pepQ<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">Rv1979c<\/jats:italic>\n                      were not. DLM\/PA variants (\n                      <jats:italic toggle=\"yes\">ddn, fbiA\u2013D,<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">fgd1<\/jats:italic>\n                      ) were frequently detected as non-fixed populations, yet rarely yielding MIC values above the CC. Predicted structural destabilization showed no consistent association with MIC values or variant fixation status. Under the conditions tested, phenotypic resistance was not detected for most group 3 and 4 variants detected by WGS. Our data provide evidence from SSA to support improved interpretation of resistance-associated mutations for new and repurposed antituberculosis drugs.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>\n                        <jats:sc>IMPORTANCE<\/jats:sc>\n                      <\/jats:title>\n                      <jats:p>\n                        Whole-genome sequencing increasingly detects\n                        <jats:italic toggle=\"yes\">Mycobacterium tuberculosis complex<\/jats:italic>\n                        mutations classified by the World Health Organization (WHO) mutation catalog v2 as group 3 variants of uncertain significance or group 4 variants not associated with resistance-interim, limiting reliable prediction of resistance to new and repurposed antituberculosis drugs. By generating minimum inhibitory concentration (MIC) data for such variants identified in a multi-country sub-Saharan African cohort, this study provides phenotypic evidence to support future refinement and expansion of the WHO mutation catalog v2. Notably,\n                        <jats:italic toggle=\"yes\">mmpR5<\/jats:italic>\n                        variants associated with elevated bedaquiline\/clofazimine MICs were identified in eight isolates, suggesting that some patients in this cohort may have harbored pre-existing resistance-associated variants yet remained potentially eligible for bedaquiline-containing regimens. These findings contribute to improving the interpretation of genomic resistance data and strengthening surveillance of resistance to bedaquiline, clofazimine, delamanid, and pretomanid.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.02005-26","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T13:00:47Z","timestamp":1785243647000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["No phenotypic resistance observed for most group-3 and -4 variants in\n                    <i>Mycobacterium tuberculosis<\/i>\n                    genes related to bedaquiline, clofazimine, delamanid, and pretomanid in a Central and West African context"],"prefix":"10.1128","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3045-3778","authenticated-orcid":true,"given":"Faridath","family":"Massou","sequence":"first","affiliation":[{"name":"Supranational Reference Laboratory of Tuberculosis","place":["Cotonou, B\u00e9nin"]},{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]},{"id":[{"id":"https:\/\/ror.org\/008x57b05","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7029-2470","authenticated-orcid":true,"given":"Klaas","family":"Dewaele","sequence":"additional","affiliation":[{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anderson","family":"Gnamy","sequence":"additional","affiliation":[{"name":"Supranational Reference Laboratory of Tuberculosis","place":["Cotonou, B\u00e9nin"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramata","family":"Balde","sequence":"additional","affiliation":[{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9566-3653","authenticated-orcid":true,"given":"Wim","family":"Mulders","sequence":"additional","affiliation":[{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor J.","family":"Mehan","sequence":"additional","affiliation":[{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]},{"id":[{"id":"https:\/\/ror.org\/04xyxjd90","id-type":"ROR","asserted-by":"publisher"}],"name":"Centre for Systems Health and Integrated Metabolic Research, Nottingham Trent University","place":["Nottingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1017-4675","authenticated-orcid":true,"given":"Bouke C.","family":"de Jong","sequence":"additional","affiliation":[{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dissou","family":"Affolabi","sequence":"additional","affiliation":[{"name":"Supranational Reference Laboratory of Tuberculosis","place":["Cotonou, B\u00e9nin"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7096-8063","authenticated-orcid":true,"given":"Oren","family":"Tzfadia","sequence":"additional","affiliation":[{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3301-9480","authenticated-orcid":true,"given":"Leen","family":"Rigouts","sequence":"additional","affiliation":[{"name":"Mycobacteriology unit, Department of Biomedical Sciences, Institute of Tropical Medicine","place":["Antwerp, Belgium"]},{"id":[{"id":"https:\/\/ror.org\/008x57b05","id-type":"ROR","asserted-by":"publisher"}],"name":"Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp","place":["Antwerp, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","volume-title":"WHO consolidated guidelines on tuberculosis. Module 4: treatment and care","author":"World Health Organization","year":"2025","unstructured":"World Health Organization. 2025. WHO consolidated guidelines on tuberculosis. Module 4: treatment and care. Geneva."},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.611683"},{"key":"e_1_3_5_4_2","volume-title":"Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance","author":"World Health Organization","year":"2023","unstructured":"World Health Organization. 2023. Catalogue of mutations in Mycobacterium tuberculosis complex and their association with drug resistance. Second"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1304857"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2018.01.005"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01611-09"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00037-14"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkw502"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.5588\/ijtld.18.0417"},{"key":"e_1_3_5_11_2","unstructured":"World Health Organization. 2025. Global tuberculosis report. Geneva"},{"key":"e_1_3_5_12_2","volume-title":"WHO operational handbook on tuberculosis. Module 3: diagnosis","author":"World Health Organization","year":"2025","unstructured":"World Health Organization. 2025. WHO operational handbook on tuberculosis. Module 3: diagnosis. Geneva."},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0102135"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkaa136"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00308-15"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01304-20"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1008287"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-015-2109-3"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2024.101156"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.01113-25"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-36955-y"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-026-39491-7"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanmic.2025.101293"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2656"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.210641.116"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-019-0650-x"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmi.2020.07.036"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00239-2022"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.01677-19"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3942"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btaf064"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792"}],"container-title":["Microbiology Spectrum"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02005-26","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.02005-26","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:12:11Z","timestamp":1788268331000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/spectrum.02005-26"}},"subtitle":[],"editor":[{"given":"Maria Elvira","family":"Balcells","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":32,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9,1]]}},"alternative-id":["10.1128\/spectrum.02005-26"],"URL":"https:\/\/doi.org\/10.1128\/spectrum.02005-26","relation":{},"ISSN":["2165-0497"],"issn-type":[{"value":"2165-0497","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"assertion":[{"value":"2026-06-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02005-26"}}