15:20–15:40 (online) .


Title: Transcontinental spread and evolution of an MDR M. tuberculosis clade over five decades

Authors: Matthias Merker1,2,3,*,Jean-Philippe Rasigade4,5,7,*, Maxime Barbier4,5,*,Helen Cox6, Silke Feuerriegel1,2, Thomas A. Kohl1,2, Egor Shitikov8, Kadri Klaos9, Cyril Gaudin10, Rudy Antoine11, Roland Diel12, Sonia Borrell13,14, Sebastien Gagneux13,14, Vladyslav Nikolayevskyy15, Sönke Andres16, Valeriu Crudu17, Ulrich Nübel18,19, Philip Supply11,#, Stefan Niemann1,2,# Thierry Wirth4,5,# * and # contributed equally

Affiliations: 1Molecular and Experimental Mycobacteriology, Research Center Borstel, Borstel, Germany; 2German Center for Infection Research, Partner site Hamburg-Lübeck-Borstel-Riems, Germany; 3Evolution of the Resistome, Research Center Borstel, Borstel, Germany; 4Laboratoire Biologie Intégrative des Populations, Evolution Moléculaire,EPHE, PSL University, Paris, France; 5Institut de Systématique, Evolution, Biodiversité, ISYEB, Muséum national d’Histoire naturelle, CNRS, Sorbonne Université, EPHE, Université des Antilles, Paris, France; 6Division of Medical Microbiology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa; 7CIRI INSERM U1111, University of Lyon, Lyon, France; 8Federal Research and Clinical Centre of Physical-Chemical Medicine, Moscow, Russian Federation; 9SA TUH United Laboratories, Mycobacteriology, Tartu, Estonia; 10Genoscreen, Lille, France; 11Univ. 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; 12Institute for Epidemiology, Schleswig-Holstein University Hospital, Kiel, Germany; 13Swiss Tropical and Public Health Institute, Basel, Switzerland; 14University of Basel, Basel, Switzerland; 15Imperial College London, London, United Kingdom; 16Division of Mycobacteriology (National Tuberculosis Reference Laboratory), Research Center Borstel, Borstel. Germany; 17National TB Reference Laboratory, Physiopneumology Institute, Chisinau, Republic of Moldova; 18Microbial Genome Research, Leibniz-Institut DSMZ- Deutsche Sammlung von Mikroorganismen und Zellkulturen, Braunschweig, Germany; 19German Center for Infection Research, Braunschweig site, Germany

Abstract: 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. Especially certain MDR clades belonging to Mtbc lineage 2 (Beijing genotype) are extremely successful in multiple settings in Eurasia.

Here, we employed comparative genomics, and Bayesian statistics of 720 isolates from 23 countries to trace the epidemic spread over time, and to identify genetic factors of transmission success of the MDR W148 European/Russian clade.

The most recent common ancestor of this clade was 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. Notably, MDR strains acquired additional resistances against fluoroquinolones and second line injectable drugs, and thus an extensively drug resistant (XDR) genotype, on average 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.

We show that the W148 European/Russian clade within Mtbc lineage 2 has evolved an outstanding genetic background which is an important factor for its’ long lasting, continent-wide epidemic success over five decades. The ongoing expansion of these strains with MDR/XDR genotypes is a challenge for phenotypic as well as genotypic antimicrobial susceptibility tests, and jeopardize the successful implementation of new MDR-TB antibiotics.