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

 Abigail L Manson  ;  Keira A Cohen  ;  Thomas Abeel  ;  Christopher A Desjardins  ;  Derek T Armstrong  ;  Clifton E Barry 3rd  ;  Jeannette Brand TBResist Global Genome Consortium  ;  Sinéad B Chapman  ;  Sang-Nae Cho  ;  Andrei Gabrielian  ;  James Gomez  ;  Andreea M Jodals  ;  Moses Joloba  ;  Pontus Jureen  ;  Jong Seok Lee  ;  Lesibana Malinga  ;  Mamoudou Maiga  ;  Dale Nordenberg  ;  Ecaterina Noroc  ;  Elena Romancenco  ;  Alex Salazar  ;  Willy Ssengooba  ;  A A Velayati  ;  Kathryn Winglee  ;  Aksana Zalutskaya  ;  Laura E Via  ;  Gail H Cassell  ;  Susan E Dorman  ;  Jerrold Ellner  ;  Parissa Farnia  ;  James E Galagan  ;  Alex Rosenthal  ;  Valeriu Crudu  ;  Daniela Homorodean  ;  Po-Ren Hsueh  ;  Sujatha Narayanan  ;  Alexander S Pym  ;  Alena Skrahina  ;  Soumya Swaminathan  ;  Martie Van der Walt  ;  David Alland  ;  William R Bishai  ;  Ted Cohen  ;  Sven Hoffner  ;  Bruce W Birren  ;  Ashlee M Earl 
 NATURE GENETICS, Vol.49(3) : 395-402, 2017-03 
Journal Title
Issue Date
Antitubercular Agents / therapeutic use ; Bacterial Proteins / genetics ; Catalase / genetics ; Drug Resistance, Multiple, Bacterial / genetics* ; Genomics / methods ; Humans ; Isoniazid / therapeutic use ; Mutation / genetics ; Mycobacterium tuberculosis / drug effects ; Mycobacterium tuberculosis / genetics* ; Polymorphism, Genetic / genetics ; Rifampin / therapeutic use ; Tuberculosis, Multidrug-Resistant / drug therapy ; Tuberculosis, Multidrug-Resistant / genetics*
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.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Cho, Sang Nae(조상래)
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