Genomic Variations in Drug Resistant Mycobacterium tuberculosis Strains Collected from Patients with Different Localization of Infection.

Ekaterina Chernyaeva,Natalia Solovieva,Ksenia Krasheninnikova,Piotr Yablonsky,Mikhail Rotkevich,Alla Lapidus,Viacheslav Zhuravlev,Stephen J O’Brien,Dmitrii E Polev

doi:10.3390/antibiotics10010027

Abstract

Mycobacterium tuberculosis is a highly studied pathogen due to public health importance. Despite this, problems like early drug resistance, diagnostics and treatment success prediction are still not fully resolved. Here, we analyze the incidence of point mutations widely used for drug resistance detection in laboratory practice and conduct comparative analysis of whole-genome sequence (WGS) for clinical M. tuberculosis strains collected from patients with pulmonary tuberculosis (PTB) and extra-pulmonary tuberculosis (XPTB) localization. A total of 72 pulmonary and 73 extrapulmonary microbiologically characterized M. tuberculosis isolates were collected from patients from 2007 to 2014 in Russia. Genomic DNA was used for WGS and obtained data allowed identifying major mutations known to be associated with drug resistance to first-line and second-line antituberculous drugs. In some cases previously described mutations were not identified. Using genome-based phylogenetic analysis we identified M. tuberculosis substrains associated with distinctions in the occurrence in PTB vs. XPTB cases. Phylogenetic analyses did reveal M. tuberculosis genetic substrains associated with TB localization. XPTB was associated with Beijing sublineages Central Asia (Beijing CAO), Central Asia Clade A (Beijing A) and 4.8 groups, while PTB localization was associated with group LAM (4.3). Further, the XPTB strain in some cases showed elevated drug resistance patterns relative to PTB isolates. HIV was significantly associated with the development of XPTB in the Beijing B0/W148 group and among unclustered Beijing isolates.

Highlights

Mycobacterium tuberculosis is one of the most widespread and studied pathogens across the globe
Our previous analysis of M. tuberculosis isolates from patients with tuberculous spondylitis showed that this group of bacterial strains is characterized by low genetic diversity and high prevalence of Beijing isolates (82% of strains belonged to the Beijing clade) [3]
Prevalence of the Beijing genetic group among extrapulmonary M. tuberculosis isolates compared to pulmonary ones was reported in a recent study, which identified Beijing in 75% of the extrapulmonary M. tuberculosis cases [14]

Summary

Introduction

Mycobacterium tuberculosis is one of the most widespread and studied pathogens across the globe. According to the WHO estimation, Russia had about 79,000 new tuberculosis (TB) cases (case rate 54 per 100,000) and 10,500 TB deaths in 2018, with 28% of new TB cases displaying multiple drug resistance or resistance to rifampicin (MDR/RR-TB) [1]. The main clinical form of tuberculosis (TB), pulmonary tuberculosis (PTB) is considered to be the most epidemically dangerous localization of the disease. For many years the proportion of patients with XPTB has remained constant with a variation of

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Conclusion