Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Allschwil, Switzerland; University of Basel, Basel, Switzerland.
Department of Plant and Microbial Biology, University of Zürich, Zürich, Switzerland.
Lancet Microbe. 2023 Jul;4(7):e506-e515. doi: 10.1016/S2666-5247(23)00110-6. Epub 2023 Jun 6.
Experimental data show that drug-resistance-conferring mutations are often associated with a decrease in the replicative fitness of bacteria in vitro, and that this fitness cost can be mitigated by compensatory mutations; however, the role of compensatory evolution in clinical settings is less clear. We assessed whether compensatory evolution was associated with increased transmission of rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa.
We did a genomic epidemiological study by analysing available M tuberculosis isolates and their associated clinical data from individuals routinely diagnosed with rifampicin-resistant tuberculosis in primary care and hospitals in Khayelitsha, Cape Town, South Africa. Isolates were collected as part of a previous study. All individuals diagnosed with rifampicin-resistant tuberculosis and with linked biobanked specimens were included in this study. We applied whole-genome sequencing, Bayesian reconstruction of transmission trees, and phylogenetic multivariable regression analysis to identify individual and bacterial factors associated with the transmission of rifampicin-resistant M tuberculosis strains.
Between Jan 1, 2008, and Dec 31, 2017, 2161 individuals were diagnosed with multidrug-resistant or rifampicin-resistant tuberculosis in Khayelitsha, Cape Town, South Africa. Whole-genome sequences were available for 1168 (54%) unique individual M tuberculosis isolates. Compensatory evolution was associated with smear-positive pulmonary disease (adjusted odds ratio 1·49, 95% CI 1·08-2·06) and a higher number of drug-resistance-conferring mutations (incidence rate ratio 1·38, 95% CI 1·28-1·48). Compensatory evolution was also associated with increased transmission of rifampicin-resistant disease between individuals (adjusted odds ratio 1·55; 95% CI 1·13-2·12), independent of other patient and bacterial factors.
Our findings suggest that compensatory evolution enhances the in vivo fitness of drug-resistant M tuberculosis genotypes, both within and between patients, and that the in vitro replicative fitness of rifampicin-resistant M tuberculosis measured in the laboratory correlates with the bacterial fitness measured in clinical settings. These results emphasise the importance of enhancing surveillance and monitoring efforts to prevent the emergence of highly transmissible clones capable of rapidly accumulating new drug resistance mutations. This concern becomes especially crucial at present, because treatment regimens incorporating novel drugs are being implemented.
Funding for this study was provided by a Swiss and South Africa joint research award (grant numbers 310030_188888, CRSII5_177163, and IZLSZ3_170834), the European Research Council (grant number 883582), and a Wellcome Trust fellowship (to HC; reference number 099818/Z/12/Z). ZS-D was funded through a PhD scholarship from the South African National Research Foundation and RMW was funded through the South African Medical Research Council.
实验数据表明，耐药性赋予突变通常与细菌在体外的复制适应性降低有关，而这种适应性成本可以通过补偿性突变来减轻；然而，补偿进化在临床环境中的作用尚不明确。我们评估了补偿进化是否与南非开普敦哈耶利特沙市利福平耐药结核病的传播增加有关。
我们通过分析南非开普敦哈耶利特沙市常规诊断为利福平耐药结核病的个体的现有 M 结核分枝杆菌分离株及其相关临床数据，进行了基因组流行病学研究。分离株是作为先前研究的一部分收集的。所有诊断为利福平耐药结核病且有相关生物银行标本的个体均纳入本研究。我们应用全基因组测序、传播树的贝叶斯重建和基于系统发育的多变量回归分析，以确定与利福平耐药 M 结核分枝杆菌菌株传播相关的个体和细菌因素。
2008 年 1 月 1 日至 2017 年 12 月 31 日期间，南非开普敦哈耶利特沙市有 2161 人被诊断患有耐多药或利福平耐药结核病。1168 个（54%）独特个体 M 结核分枝杆菌分离株有全基因组序列。补偿进化与痰涂片阳性的肺疾病（调整后的优势比 1.49，95%CI 1.08-2.06）和更多的耐药性赋予突变（发病率比 1.38，95%CI 1.28-1.48）相关。补偿进化也与个体之间利福平耐药疾病的传播增加有关（调整后的优势比 1.55；95%CI 1.13-2.12），这独立于其他患者和细菌因素。
我们的研究结果表明，补偿进化增强了耐药 M 结核分枝杆菌基因型在体内和个体之间的适应性，并且在实验室中测量的利福平耐药 M 结核分枝杆菌的体外复制适应性与在临床环境中测量的细菌适应性相关。这些结果强调了加强监测和监测工作以防止具有快速积累新耐药突变能力的高传染性克隆出现的重要性。目前，由于正在实施包含新药物的治疗方案，这种担忧变得尤为重要。
这项研究得到了瑞士和南非联合研究奖（拨款号 310030_188888、CRSII5_177163 和 IZLSZ3_170834）、欧洲研究委员会（拨款号 883582）和惠康信托基金会奖学金（HC；参考号 099818/Z/12/Z）的资助。ZS-D 通过南非国家研究基金会的博士奖学金获得资助，RMW 通过南非医学研究理事会获得资助。
