Comprehensive genomic analysis of Mycobacterium tuberculosis reveals limited impact of high-fitness genotypes on MDR-TB transmission

Objectives: Environmental and host-related factors that contribute to the transmission of multidrugresistant tuberculosis (MDR-TB) have become an increasing concern, but the impact of bacterial genetic factors associated with bacterial fitness on MDR-TB transmission is poorly understood. Here, we present a global view of the correlation between common fitness-related genotypes and MDR-TB transmission by analyzing a representative number of MDR-TB isolates. Methods: We assembled a global whole genome sequencing (WGS) dataset of MDR-TB strains collected through retrospective cohorts or population-based approaches using public databases and literature curation. WGS-based clusters were defined as groups of strains with genomic difference of ??? 5 SNPs. Results: We curated high-quality WGS data of 4696 MDR-TB isolates from 17 countries with a mean clustering rate of 48% (range 0-10 0%). Correlational analysis showed that increased risk of MDR-TB strain clustering was not associated with compensatory mutations (OR 1.07, 95% CI 0.72-1.59), low-fitness cost drug-resistant mutations ( katG S315T: OR 1.42, 95% CI 0.82-2.47; rpoB S450L: OR 1.26, 95% CI 0.87-1.83) or Lineage 2 (OR 1.50, 95% CI 0.95-2.39). Conclusions: The factors most commonly thought to increase bacterial fitness were not significantly associated with increased MDR-TB transmission, and thus do not appear to be major contributors to the current epidemic of MDR-TB. ?? 2022 The British Infection Association. Published by Elsevier Ltd. All rights reserved.