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

Nature genetics, Volume: 49, Issue: 3
March 16, 2017
Abigail L Manson AL, Keira A Cohen KA, Thomas Abeel T, Christopher A Desjardins CA, Derek T Armstrong DT, Clifton E Barry CE, Jeannette Brand J, , Sinéad B Chapman SB, Sang-Nae Cho SN, Andrei Gabrielian A, James Gomez J, Andreea M Jodals AM, Moses Joloba M, Pontus Jureen P, Jong Seok Lee JS, Lesibana Malinga L, Mamoudou Maiga M, Dale Nordenberg D, Ecaterina Noroc E, Elena Romancenco E, Alex Salazar A, Willy Ssengooba W, A A Velayati AA, Kathryn Winglee K, Aksana Zalutskaya A, Laura E Via LE, Gail H Cassell GH, Susan E Dorman SE, Jerrold Ellner J, Parissa Farnia P, James E Galagan JE, Alex Rosenthal A, Valeriu Crudu V, Daniela Homorodean D, Po-Ren Hsueh PR, Sujatha Narayanan S, Alexander S Pym AS, Alena Skrahina A, Soumya Swaminathan S, Martie Van der Walt M, David Alland D, William R Bishai WR, Ted Cohen T, Sven Hoffner S, Bruce W Birren BW, Ashlee M Earl AM

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.

Courtesy of the U.S. National Library of Medicine