Cross-sectional whole-genome sequencing and epidemiological study of multidrug-resistant Mycobacterium tuberculosis in China.

Background: The increase in MDR-TB severely hampers TB prevention and control in China, a country with the second highest MDR-TB burden globally. The first nationwide drug-resistant TB surveillance program provides an opportunity to comprehensively investigate the epidemiological/drug-resistance characteristics, potential drug-resistance mutations, and effective population changes of Chinese MDR-TB.

Methods: We sequenced 357 MDR strains from 4,600 representative TB-positive sputum samples collected from the survey (70 counties in 31 provinces). Drug-susceptibility testing was performed using 18 anti-tuberculosis drugs, representing the most comprehensive drug-resistance profile to date. We employed three statistical methods and one machine learning method to identify drug-resistance genes/SNPs. Bayesian skyline analysis investigated the changes in effective population size.

Results: Epidemiological/drug-resistance characteristics showed different multidrug-resistance profiles, co-resistance patterns, preferred drug combination/use, and recommended regimens among seven Chinese administrative regions. These not only reflected the serious multidrug co-resistance and drug misuse in some regions but these factors were also potentially significant in facilitating the development of appropriate regimens for MDR-TB treatment in China. Further investigation identified 86 drug-resistance genes/intergenic regions/SNPs (58 new), providing potential targets for diagnosis and treatment of MDR-TB. In addition, the effective population of Chinese MDR-TB displayed a strong expansion during 1993-2000, reflecting socioeconomic transition within the country. The phenomenon of expansion was restrained after 2000, likely attributable to the advances in diagnosis/treatment technologies and government support.

Conclusions: Our findings provide an important reference and improved understanding of MDR-TB in China, potentially significant in achieving the goal of precision medicine with respect to MDR-TB prevention and treatment.