P67
Evolution and spread of the multidrug resistant Mycobacterium tuberculosis W148 European/Russian clade over five decades
M Merker(1,2,3) J P Rasigade(4,5,6) M Barbier(4,5) H Cox(7) S Feuerriegel(1,2) T A Kohl(1,2) E Shitikov(8) K Klaos(9) C Gaudin(10) R Antoine(11) R Diel(12) S Borrell(13,14) S Gagneux(13,14) V Nikolayevskyy(15) S Andres(16) V Crudu(17) P Supply(11) S Niemann(1,2) T Wirth(4,5)
1:Molecular and Experimental Mycobacteriology, Research Center Borstel, Germany; 2:German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Germany.; 3:Evolution of the Resistome, Research Center Borstel, Germany; 4:EPHE, PSL University, Paris, France; 5:Institut de Systématique, Evolution, Biodiversité, ISYEB, Muséum national d’Histoire naturelle, CNRS, Sorbonne Université, EPHE, Université des Antilles, Paris, France; 6:Centre International de Recherche en Infectiologie, INSERM U1111, CNRS UMR5308, Université Lyon 1, ENS de Lyon, Lyon, France; 7:Division of Medical Microbiology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa; 8:Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow, Russian Federation; 9:SA TUH United Laboratories, Mycobacteriology, Tartu, Estonia; 10:Genoscreen, Lille, France; 11:Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000 Lille, France; 12:Institute for Epidemiology, Schleswig-Holstein University Hospital, Kiel, Germany; 13:Swiss Tropical and Public Health Institute, Basel, Switzerland.; 14:University of Basel, Basel, Switzerland.; 15:Imperial College London, United Kingdom; 16:Division of Mycobacteriology (National Tuberculosis Reference Laboratory), Research Center Borstel, Borstel. Germany; 17:National TB Reference Laboratory, Physiopneumology Institute, Chisinau, Republic of Moldova
Transmission and evolution of multidrug resistant (MDR) Mycobacterium tuberculosis complex (Mtbc) strains are jeopardizing the long-term efficacy of new antibiotics and newly endorsed combination therapies. We employed comparative genomics, and Bayesian statistics of 720 outbreak isolates from 23 countries to trace the transcontinental spread and identify genetic factors of transmission success of the MDR W148 European/Russian clade.
The most recent common ancestor dated around 1963 and the bacterial population underwent two successive epidemic expansion events in the late 1980s and late 1990s. These population expansions were accompanied by the evolution of resistance against up to 11 different anti-TB drugs. On average MDR strains acquired additional resistances to fluoroquinolones and second-line injectable drugs within 20 years. Time-scaled haplotypic density analysis, as a surrogate marker for recent expansion events, revealed that widespread acquisition of compensatory mutations was associated with transmission success, particularly of the most resistant W148 strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. This outstanding genetic background together with its long lasting, continent-wide epidemic success over five decades also jeopardizes new MDR-TB therapies, and challenges phenotypic as well as genotypic antimicrobial susceptibility tests.