Genomic analysis of globally diverse Mycobacterium tuberculosis strains provides insights into the emergence and spread of multidrug resistance
Journal
Nature Genetics
Journal Volume
49
Journal Issue
3
Pages
395-402
Date Issued
2017
Author(s)
Manson A.L.
Cohen K.A.
Abeel T.
Desjardins C.A.
Armstrong D.T.
Barry C.E.
Brand J.
Chapman S.B.
Cho S.-N.
Gabrielian A.
Gomez J.
Jodals A.M.
Joloba M.
Jureen P.
Lee J.S.
Malinga L.
Maiga M.
Nordenberg D.
Noroc E.
Romancenco E.
Salazar A.
Ssengooba W.
Velayati A.A.
Winglee K.
Zalutskaya A.
Via L.E.
Cassell G.H.
Dorman S.E.
Ellner J.
Farnia P.
Galagan J.E.
Rosenthal A.
Crudu V.
Homorodean D.
Narayanan S.
Pym A.S.
Skrahina A.
Swaminathan S.
Van Der Walt M.
Alland D.
Bishai W.R.
Cohen T.
Hoffner S.
Birren B.W.
Earl A.M.
Abstract
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.
SDGs
Other Subjects
ethambutol; ethionamide; isoniazid; kanamycin; KatG protein; ofloxacin; pyrazinamide; rifampicin; serine; streptomycin; thyroxine; bacterial protein; catalase; isoniazid; katG protein, Mycobacterium tuberculosis; rifampicin; tuberculostatic agent; antibiotic resistance; Article; bacterial genome; bacterial mutation; bacterial strain; bacterium isolation; gene sequence; genetic analysis; genetic background; genomics; human; molecular diagnosis; multidrug resistance; multidrug resistant tuberculosis; Mycobacterium tuberculosis; priority journal; whole genome sequencing; drug effects; genetic polymorphism; genetics; multidrug resistance; mutation; Mycobacterium tuberculosis; procedures; Tuberculosis, Multidrug-Resistant; Antitubercular Agents; Bacterial Proteins; Catalase; Drug Resistance, Multiple, Bacterial; Genomics; Humans; Isoniazid; Mutation; Mycobacterium tuberculosis; Polymorphism, Genetic; Rifampin; Tuberculosis, Multidrug-Resistant
Type
journal article