Cross-sectional Whole-genome Sequencing and Epidemiological Study of Multidrug-resistant Mycobacterium tuberculosis in China.

BACKGROUND: The increase in multidrug-resistant tuberculosis (MDR-TB) severely hampers tuberculosis prevention and control in China, a country with the second highest MDR-TB burden globally. The first nationwide drug-resistant tuberculosis 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 4600 representative tuberculosis-positive sputum samples collected during 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 used 3 statistical and 1 machine-learning methods to identify drug-resistance genes/single-nucleotide polymorphisms (SNPs). We used Bayesian skyline analysis to investigate changes in effective population size. RESULTS: Epidemiological/drug-resistance characteristics showed different MDR profiles, co-resistance patterns, preferred drug combination/use, and recommended regimens among 7 Chinese administrative regions. These factors not only reflected the serious multidrug co-resistance and drug misuse but they 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 MDR-TB diagnosis and treatment. 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, which are potentially significant in achieving the goal of precision medicine with respect to MDR-TB prevention and treatment.