Compensatory Mutations of Rifampin Resistance Are Associated with Transmission of Multidrug-Resistant Mycobacterium tuberculosis Beijing Genotype Strains in China

Mycobacterium tuberculosis can acquire resistance to rifampin (RIF) through mutations in therpoB gene. This is usually accompanied by a fitness cost, which, however, can be mitigated by secondary mutations in therpoA orrpoC gene. This study aimed to identifyrpoA andrpoC mutations in clinicalM. tuberculosis isolates in northern China in order to clarify their role in the transmission of drug-resistant tuberculosis (TB). The study collection included 332 RIF-resistant and 178 RIF-susceptible isolates. The majority of isolates belonged to the Beijing genotype (95.3%, 486/510 isolates), and no mutation was found inrpoA orrpoC of the non-Beijing genotype strains. Among the Beijing genotype strains, 27.8% (89/320) of RIF-resistant isolates harbored nonsynonymous mutations in therpoA (n = 6) orrpoC (n = 83) gene. The proportion ofrpoC mutations was significantly higher in new cases (P = 0.023) and in strains with therpoB S531L mutation (P < 0.001). In addition, multidrug-resistant (MDR) strains withrpoC mutations were significantly associated with 24-locus mycobacterial interspersed repetitive-unit–variable-number tandem-repeat clustering (P = 0.016). In summary, we believe that these findings indirectly suggest an epistatic interaction of particular mutations related to RIF resistance and strain fitness and, consequently, the role of such mutations in the spread of MDRM. tuberculosis strains.