Genetic Diversity of Multi- and Extensively Drug-Resistant Mycobacterium tuberculosis Isolates in the Capital of Iran, Revealed by Whole-Genome Sequencing

Abstract

The emergence and spread of multidrug resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains is a critical global health problem. Between 2014 and 2018, 606 MTBC strains were isolated from 13,892 suspected pulmonary tuberculosis (TB) patients in Tehran, Iran, including 16 (2.6%) MDR-TB cases. A combination of phenotypic and genotypic methods (whole-genome sequencing) was employed for the identification of additional drug resistances and strain-to-strain genetic distances as a marker for recent transmission events. MDR and extensively drug-resistant (XDR) TB cases were almost exclusively infected by lineage 2/Beijing strains (14/16, P < 0.001). We further showed that recent transmission and/or recent introduction of lineage 2/Beijing strains contribute to high XDR-TB rates among all MDR-TB cases and should be considered an emerging threat for TB control in Tehran. In addition, the extensive pre-existing drug resistance profiles of MDR/XDR strains will further challenge TB diagnostics in the region.

Keywords: Mycobacterium tuberculosis; Tehran; extensive drug resistance; multidrug resistance; whole-genome sequencing.

FIG 1

Maximum likelihood tree constructed from 5,660 SNP positions of the 38 isolates. Branches of the tree are colored according to major Mycobacterium tuberculosis lineages (Beijing, Delhi/CAS, and Euro-American). The boxes are color coded for distinct genetic drug resistance markers and bacterial fitness-associated (compensatory [COMP]) mutations (i.e., one color indicates a specific variant related). INH, isoniazid; RIF, rifampin; Sm, streptomycin; EMB, ethambutol; PZA, pyrazinamide; Km, Kanamycin; Am, amikacin; Cm, capreomycin; FQ, fluoroquinolone; Eto, ethionamide; Pto, prothionamide; PAS, para-aminosalicylic acid.