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Nat Genet DOI:10.1038/ng.3767

Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance.

Publication TypeJournal Article
Year of Publication2017
AuthorsManson, AL, Cohen, KA, Abeel, T, Desjardins, CA, Armstrong, DT, Barry, CE, Brand, J, Chapman, SB, Cho, S-N, Gabrielian, A, Gomez, J, Jodals, AM, Joloba, M, Jureen, P, Lee, JSeok, Malinga, L, Maiga, M, Nordenberg, D, Noroc, E, Romancenco, E, Salazar, A, Ssengooba, W, Velayati, AA, Winglee, K, Zalutskaya, A, Via, LE, Cassell, GH, Dorman, SE, Ellner, J, Farnia, P, Galagan, JE, Rosenthal, A, Crudu, V, Homorodean, D, Hsueh, P-R, Narayanan, S, Pym, AS, Skrahina, A, Swaminathan, S, Van der Walt, M, Alland, D, Bishai, WR, Cohen, T, Hoffner, S, Birren, BW, Earl, AM
Corporate AuthorsTBResist Global Genome Consortium
JournalNat Genet
Date Published2017 Mar

Multidrug-resistant tuberculosis (MDR-TB), caused by drug-resistant strains of Mycobacterium tuberculosis, is an increasingly serious problem worldwide. Here we examined a data set of whole-genome sequences from 5,310 M. tuberculosis isolates from five continents. Despite the great diversity of these isolates with respect to geographical point of isolation, genetic background and drug resistance, the patterns for the emergence of drug resistance were conserved globally. We have identified harbinger mutations that often precede multidrug resistance. In particular, the katG mutation encoding p.Ser315Thr, which confers resistance to isoniazid, overwhelmingly arose before mutations that conferred rifampicin resistance across all of the lineages, geographical regions and time periods. Therefore, molecular diagnostics that include markers for rifampicin resistance alone will be insufficient to identify pre-MDR strains. Incorporating knowledge of polymorphisms that occur before the emergence of multidrug resistance, particularly katG p.Ser315Thr, into molecular diagnostics should enable targeted treatment of patients with pre-MDR-TB to prevent further development of MDR-TB.


Alternate JournalNat. Genet.
PubMed ID28092681
Grant ListR01 AI110386 / AI / NIAID NIH HHS / United States
U19 AI110818 / AI / NIAID NIH HHS / United States