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Drug-susceptibility tests for some anti-TB drugs, especially ethambutol (ETH) and ethionamide (ETO), are problematic due to overlapping thresholds to differentiate between susceptible and resistant phenotypes. We aimed to identify possible metabolomic markers to detect <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>Mtb<\/jats:italic>) strains causing pre-XDR and XDR-TB. The metabolic patterns of ETH- and ETO-resistant <jats:italic>Mtb<\/jats:italic> isolates were also investigated. Metabolomics of 150 <jats:italic>Mtb<\/jats:italic> isolates (54 pre-XDR, 63 XDR-TB and 33 pan-susceptible; pan-S) were investigated. Metabolomics of ETH and ETO phenotypically resistant subgroups were analyzed using UHPLC-ESI-QTOF-MS\/MS. Orthogonal partial least-squares discriminant analysis revealed distinct separation in all pairwise comparisons among groups. Two metabolites (meso-hydroxyheme and itaconic anhydride) were able to differentiate the pre-XDR and XDR-TB groups from the pan-S group with 100% sensitivity and 100% specificity. In comparisons of the ETH and ETO phenotypically resistant subsets, sets of increased (ETH\u2009=\u200915, ETO\u2009=\u20097) and decreased (ETH\u2009=\u20091, ETO\u2009=\u20096) metabolites specific for the resistance phenotype of each drug were found. We demonstrated the potential for metabolomics of <jats:italic>Mtb<\/jats:italic> to differentiate among types of DR-TB as well as between isolates that were phenotypically resistant to ETO and ETH. Thus, metabolomics might be further applied for DR-TB diagnosis and patient management.<\/jats:p>","DOI":"10.1038\/s41598-023-35882-2","type":"journal-article","created":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T17:01:51Z","timestamp":1685206911000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Metabolomic analysis of Mycobacterium tuberculosis reveals metabolic profiles for identification of drug-resistant tuberculosis"],"prefix":"10.1038","volume":"13","author":[{"given":"Pratchakan","family":"Chaiyachat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjawan","family":"Kaewseekhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angkana","family":"Chaiprasert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phalin","family":"Kamolwat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ditthawat","family":"Nonghanphithak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutarop","family":"Phetcharaburanin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Auttawit","family":"Sirichoat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rick Twee-Hee","family":"Ong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiatichai","family":"Faksri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,27]]},"reference":[{"key":"35882_CR1","unstructured":"World Health Organization, Global Tuberculosis Report 2021, Geneva, Switzerland (2021)."},{"key":"35882_CR2","unstructured":"Organization, W. 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