Song Zexuan, Liu Chunfa, He Wencong, Pei Shaojun, Liu Dongxin, Cao Xiaolong, Wang Yiting, He Ping, Zhao Bing, Ou Xichao, Xia Hui, Wang Shengfen, Zhao Yanlin
National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention , Beijing, China.
National Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention , Beijing, China.
Microbiol Spectr. 2023 Sep 21;11(5):e0132423. doi: 10.1128/spectrum.01324-23.
Multidrug-resistant tuberculosis (MDR-TB) has a severe impact on public health. To investigate the drug-resistant profile, compensatory mutations and genetic variations among MDR-TB isolates, a total of 546 MDR-TB isolates from China underwent drug-susceptibility testing and whole genome sequencing for further analysis. The results showed that our isolates have a high rate of fluoroquinolone resistance (45.60%, 249/546) and a low proportion of conferring resistance to bedaquiline, clofazimine, linezolid, and delamanid. The majority of MDR-TB isolates (77.66%, 424/546) belong to Lineage 2.2.1, followed by Lineage 4.5 (6.41%, 35/546), and the Lineage 2 isolates have a strong association with pre-XDR/XDR-TB ( < 0.05) in our study. Epidemic success analysis using time-scaled haplotypic density (THD) showed that clustered isolates outperformed non-clustered isolates. Compensatory mutations happened in , and non-RRDR of genes, which were found more frequently in clusters and were associated with the increase of THD index, suggesting that increased bacterial fitness was associated with MDR-TB transmission. In addition, the variants in resistance associated genes in MDR isolates are mainly focused on single nucleotide polymorphism mutations, and only a few genes have indel variants, such as , . We also found some genes underwent indel variation correlated with the lineage and sub-lineage of isolates, suggesting the selective evolution of different lineage isolates. Thus, this analysis of the characterization and genetic diversity of MDR isolates would be helpful in developing effective strategies for treatment regimens and tailoring public interventions. IMPORTANCE Multidrug-resistant tuberculosis (MDR-TB) is a serious obstacle to tuberculosis prevention and control in China. This study provides insight into the drug-resistant characteristics of MDR combined with phenotypic drug-susceptibility testing and whole genome sequencing. The compensatory mutations and epidemic success analysis were analyzed by time-scaled haplotypic density (THD) method, suggesting clustered isolates and compensatory mutations are associated with MDR-TB transmission. In addition, the insertion and deletion variants happened in some genes, which are associated with the lineage and sub-lineage of isolates, such as the gene. This study offered a valuable reference and increased understanding of MDR-TB in China, which could be crucial for achieving the objective of precision medicine in the prevention and treatment of MDR-TB.
耐多药结核病（MDR-TB）对公共卫生有严重影响。为了研究耐多药结核分枝杆菌分离株的耐药谱、补偿性突变和基因变异情况，对来自中国的546株耐多药结核分枝杆菌分离株进行了药敏试验和全基因组测序以作进一步分析。结果显示，我们的分离株对氟喹诺酮类药物耐药率较高（45.60%，249/546），而对贝达喹啉、氯法齐明、利奈唑胺和德拉马尼耐药的比例较低。大多数耐多药结核分枝杆菌分离株（77.66%，424/546）属于2.2.1家族，其次是4.5家族（6.41%，35/546），在我们的研究中，2家族分离株与广泛耐药/极度耐药结核病（<0.05）有很强的相关性。使用时间尺度单倍型密度（THD）进行的流行成功分析表明，聚集性分离株比非聚集性分离株表现更好。补偿性突变发生在基因的、和非RRDR区域，在聚集性分离株中更频繁地被发现，并且与THD指数的增加相关，这表明细菌适应性的增加与耐多药结核的传播有关。此外，耐多药分离株中耐药相关基因的变异主要集中在单核苷酸多态性突变上，只有少数基因有插入缺失变异，如、。我们还发现一些基因发生的插入缺失变异与分离株的家族和亚家族相关，表明不同家族分离株的选择性进化。因此，对耐多药分离株的特征和遗传多样性进行分析将有助于制定有效的治疗方案策略和调整公共干预措施。重要性 耐多药结核病（MDR-TB）是中国结核病防控的严重障碍。本研究结合表型药敏试验和全基因组测序，深入了解了耐多药结核的耐药特征。通过时间尺度单倍型密度（THD）方法对补偿性突变和流行成功进行了分析，表明聚集性分离株和补偿性突变与耐多药结核的传播有关。此外，一些基因发生了插入缺失变异，这些变异与分离株的家族和亚家族相关，如基因。本研究为了解中国的耐多药结核病提供了有价值的参考，对于实现耐多药结核病防治的精准医学目标可能至关重要。
