Long-term spatiotemporal evolution of drug-resistant Mycobacterium tuberculosis in China

Antibiotics have been used to treat tuberculosis for over 80 years, yet the long-term evolutionary dynamics of Mycobacterium tuberculosis (Mtb) under antibiotic pressure remain poorly characterized at the population level. Here, we analyze more than 18,000 available Mtb genomes to reconstruct the temporal and spatial evolution of drug resistance across China. We observe that resistance mutations to different drugs arose repeatedly, giving rise to hundreds to over a thousand small drug-resistant clades that mostly emerged within the past two decades. Once established, transmission of these clades was predominantly sustained within provinces, but could expand geographically with increased human mobility and bacterial fitness. In addition, we integrate published genomic and CRISPRi screening data to identify mutations associated with the emergence and transmission of drug resistance. Our study highlights the importance of human migration and bacterial adaptation in shaping local epidemics of drug-resistant tuberculosis in China.