{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:59:01Z","timestamp":1791223141852,"version":"4.1.0"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5D43TW007124-19"],"award-info":[{"award-number":["5D43TW007124-19"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Emerging resistance to delamanid (DLM) and pretomanid (Pa) threatens drug-resistant tuberculosis (DR-TB) treatment outcomes. The lack of rapid molecular diagnostics, due to limited knowledge of resistance-conferring mutations, along with standardization challenges for critical concentrations (CC) in phenotypic drug susceptibility testing (pDST) hinder resistance detection. Here, we explore the correlation between minimum inhibitory concentrations (MICs) and genomic variants of DLM and Pa resistance in\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    (\n                    <jats:italic>Mtb<\/jats:italic>\n                    )\n                    <jats:italic>.<\/jats:italic>\n                    Seventeen\n                    <jats:italic>Mtb<\/jats:italic>\n                    isolates phenotypically resistant to DLM detected through routine pDST using the Mycobacterial Growth Indicator Tube (MGIT) system from 2021\u20132024 were selected from the National Reference Laboratory biobank in Tbilisi, Georgia. DLM\/Pa MICs were determined using the Resazurin Microtiter Assay (REMA) with a DLM concentration range of 0.008\u20132 \u00b5g\/ml, and a broader range of 0.125\u201332 \u00b5g\/ml was utilized for Pa. To identify mutations associated with DLM\/Pa resistance, isolates were subjected to whole genome sequencing (WGS). Of the seventeen\n                    <jats:italic>Mtb<\/jats:italic>\n                    isolates phenotypically resistant to DLM, eight (47%) manifested a MIC value below the DLM CC (0.06 \u00b5g\/ml), with only one carrying a mutation in a gene associated with DLM\/Pa resistance (\n                    <jats:italic>fbiC<\/jats:italic>\n                    ). Among the remaining nine isolates with MICs above the CC, the premature stop codon mutation W88* in\n                    <jats:italic>ddn<\/jats:italic>\n                    gene predominated, present in five cases and associated with elevated DLM and Pa MICs (0.125\u20132 \u00b5g\/ml and 2\u20138 \u00b5g\/ml, respectively). Three isolates (19%) harbored novel, previously undescribed genetic variants, all within genes previously linked to resistance DLM\/Pa (G35fs in\n                    <jats:italic>ddn<\/jats:italic>\n                    , Q317R and Q279H in\n                    <jats:italic>fgd1<\/jats:italic>\n                    , and C565W in\n                    <jats:italic>fbiC<\/jats:italic>\n                    ). Our results support DLM and Pa resistance association with W88* and W678G mutations in\n                    <jats:italic>ddn<\/jats:italic>\n                    and\n                    <jats:italic>fbiC<\/jats:italic>\n                    genes respectively, currently graded as \u201cuncertain significance\u201d in the WHO catalogue of\n                    <jats:italic>Mtb<\/jats:italic>\n                    drug resistance-conferring mutations. Additionally, we observed previously undescribed mutations exclusively within genes linked to DLM\/Pa susceptibility, prompting further investigation of their role in resistance.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0359717","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:42:56Z","timestamp":1791222176000},"page":"e0359717","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Associating Mycobacterium tuberculosis genomic variants with minimum inhibitory concentrations to delamanid and pretomanid"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4111-6475","authenticated-orcid":true,"given":"Ana","family":"Tsutsunava","sequence":"first","affiliation":[{"name":"National Center for Lung Health (NCLH)","place":["Tbilisi, Georgia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nestani","family":"Tukvadze","sequence":"additional","affiliation":[{"name":"National Center for Lung Health (NCLH)","place":["Tbilisi, Georgia"]},{"name":"Swiss Tropical and Public Health Institute (Swiss TPH)","place":["Allschwil, Switzerland"]},{"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaza","family":"Avaliani","sequence":"additional","affiliation":[{"name":"National Center for Lung Health (NCLH)","place":["Tbilisi, Georgia"]},{"name":"European University","place":["Tbilisi, Georgia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galo A.","family":"Goig","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute (Swiss TPH)","place":["Allschwil, Switzerland"]},{"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Levan","family":"Jugheli","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute (Swiss TPH)","place":["Allschwil, Switzerland"]},{"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastien","family":"Gagneux","sequence":"additional","affiliation":[{"name":"Swiss Tropical and Public Health Institute (Swiss TPH)","place":["Allschwil, Switzerland"]},{"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7188-4996","authenticated-orcid":true,"given":"Russell R.","family":"Kempker","sequence":"additional","affiliation":[{"name":"Emory University School of Medicine","place":["Atlanta, Georgia, United States of America"],"department":["Division of Infectious Diseases, Department of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1227-1900","authenticated-orcid":true,"given":"Nino","family":"Maghradze","sequence":"additional","affiliation":[{"name":"National Center for Lung Health (NCLH)","place":["Tbilisi, Georgia"]},{"name":"Swiss Tropical and Public Health Institute (Swiss TPH)","place":["Allschwil, Switzerland"]},{"name":"University of Basel","place":["Basel, Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"pone.0359717.ref001","volume-title":"Global tuberculosis report 2025","author":"World Health Organization","year":"2025"},{"issue":"1","key":"pone.0359717.ref002","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/ddr.21498","article-title":"Bedaquiline and delamanid in the treatment of multidrug-resistant tuberculosis: Promising but challenging","volume":"80","author":"Y Li","year":"2019","journal-title":"Drug Dev Res"},{"key":"pone.0359717.ref003","doi-asserted-by":"crossref","DOI":"10.1093\/cid\/ciac528","article-title":"Bedaquiline, Delamanid, Linezolid, and Clofazimine for treatment of pre-extensively drug-resistant tuberculosis","volume":"76","author":"C Padmapriyadarsini","year":"2023","journal-title":"Clinical Infectious Diseases"},{"issue":"1","key":"pone.0359717.ref004","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1056\/NEJMc2404644","article-title":"Transmission as a key driver of resistance to the new tuberculosis drugs","volume":"392","author":"GA Goig","year":"2025","journal-title":"N Engl J Med"},{"issue":"4","key":"pone.0359717.ref005","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1093\/jac\/dkab505","article-title":"Delamanid or pretomanid? A Solomonic judgement!","volume":"77","author":"SE Mudde","year":"2022","journal-title":"J Antimicrob Chemother"},{"key":"pone.0359717.ref006","author":"U.S. Food and Drug Administration","year":"2019"},{"key":"pone.0359717.ref007","volume-title":"WHO consolidated guidelines on tuberculosis: Module 4: Treatment: drug-resistant tuberculosis treatment","author":"World Health Organization","year":"2020"},{"issue":"9","key":"pone.0359717.ref008","doi-asserted-by":"crossref","first-page":"5316","DOI":"10.1128\/AAC.00308-15","article-title":"Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of Mycobacterium tuberculosis","volume":"59","author":"HL Haver","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"key":"pone.0359717.ref009","doi-asserted-by":"crossref","first-page":"3252","DOI":"10.1093\/cid\/ciaa755","article-title":"Delamanid resistance: update and clinical management","volume":"71","author":"TVA Nguyen","year":"2020","journal-title":"Clinical Infectious Diseases"},{"issue":"8","key":"pone.0359717.ref010","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1093\/jac\/dkaa136","article-title":"Systematic review of mutations associated with resistance to the new and repurposed Mycobacterium tuberculosis drugs bedaquiline, clofazimine, linezolid, delamanid and pretomanid","volume":"75","author":"S Kadura","year":"2020","journal-title":"J Antimicrob Chemother"},{"issue":"1","key":"pone.0359717.ref011","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.01948-20","article-title":"Mutations in fbiD (Rv2983) as a novel determinant of resistance to pretomanid and delamanid in Mycobacterium tuberculosis","volume":"65","author":"D Rifat","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"issue":"12","key":"pone.0359717.ref012","article-title":"Spontaneous mutational patterns and novel mutations for delamanid resistance in Mycobacterium tuberculosis","volume":"66","author":"Y Liu","year":"2022","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pone.0359717.ref013","doi-asserted-by":"crossref","first-page":"3828","DOI":"10.1038\/s41467-023-39300-z","article-title":"DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid","volume":"14","author":"KA Abrahams","year":"2023","journal-title":"Nat Commun"},{"key":"pone.0359717.ref014","volume-title":"Technical report on critical concentrations for drug susceptibility testing of medicines used in the treatment of drug-resistant tuberculosis","author":"World Health Organization","year":"2018"},{"issue":"6","key":"pone.0359717.ref015","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1093\/jac\/dkac070","article-title":"Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid","volume":"77","author":"A Bateson","year":"2022","journal-title":"J Antimicrob Chemother"},{"issue":"10","key":"pone.0359717.ref016","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1056\/NEJMoa1901814","article-title":"Treatment of highly drug-resistant pulmonary tuberculosis","volume":"382","author":"F Conradie","year":"2020","journal-title":"N Engl J Med"},{"issue":"4","key":"pone.0359717.ref017","doi-asserted-by":"crossref","first-page":"106953","DOI":"10.1016\/j.ijantimicag.2023.106953","article-title":"Pretomanid resistance: An update on emergence, mechanisms and relevance for clinical practice","volume":"62","author":"TVA Nguyen","year":"2023","journal-title":"Int J Antimicrob Agents"},{"key":"pone.0359717.ref018","volume-title":"WHO operational handbook on tuberculosis. Module 3: Diagnosis \u2013 rapid diagnostics for tuberculosis detection. 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Module 4: Treatment and care","author":"World Health Organization","year":"2025"},{"key":"pone.0359717.ref031","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.00900-17","article-title":"In Vitro drug susceptibility of bedaquiline, delamanid, linezolid, clofazimine, moxifloxacin, and gatifloxacin against extensively drug-resistant tuberculosis in Beijing, China","volume":"61","author":"Y Pang","year":"2017","journal-title":"Antimicrobial Agents and Chemotherapy"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0359717","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:43:02Z","timestamp":1791222182000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0359717"}},"subtitle":[],"editor":[{"given":"Divakar","family":"Sharma","sequence":"first","affiliation":[{"name":"Lady Hardinge Medical College","place":["INDIA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":31,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,10,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0359717","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]}}}