Sun Honghu, Zeng Jumei, Li Song, Liang Pengkuan, Zheng Chao, Liu Yong, Luo Tao, Rastogi Nalin, Sun Qun
Key Laboratory of Bio-Resources and Eco-Environment of the Ministry of Education, College of Life Sciences, Sichuan University.
Chengdu Institutes for Food and Drug Control, Chengdu, Sichuan, People's Republic of China.
Infect Drug Resist. 2018 Mar 27;11:431-440. doi: 10.2147/IDR.S152335. eCollection 2018.
The interaction between different drug-resistant mutations is important to the development of drug resistance and its evolution. In this study, we aimed to reveal the potential relationships between mutations conferring resistance to two important antituberculosis drugs streptomycin (STR) and fluoroquinolones (FLQ).
We used an in vitro competitive fitness assay to reveal the interactions between different mutations of and in drug-resistant , followed by the analysis of the frequency of and mutation combinations in 213 STR-FLQ dual-resistant clinical isolates from Sichuan region, which was also investigated by the whole genome data from 3,056 global clinical isolates.
The strains with K43R and K88R mutation in showed no difference in relative fitness compared with their susceptible ancestor, while K43N, K43M, K43T, and K88E exhibited a significantly lower relative fitness (<0.05). For the FLQ-resistant mutants, all mutation types showed no difference in their relative fitness. Among STR-FLQ dual-resistant strains, a lower fitness was detected in those with K43N/M/T and K88E instead of K43R and K88R mutations in . Among isolates harboring and dual mutations, the most two frequent combinatorial mutation types were K43R/D94G (n=37) and K43R/A90V (n=24), with the former being the most frequent one by both in vitro tests and clinical survey.
Our results suggest that the interaction between and mutations affects the fitness cost in STR-FLQ dual-resistant and also the predilection of mutation combinations in clinical isolates.
不同耐药突变之间的相互作用对于耐药性的产生及其演变至关重要。在本研究中，我们旨在揭示赋予对两种重要抗结核药物链霉素（STR）和氟喹诺酮类（FLQ）耐药性的突变之间的潜在关系。
我们使用体外竞争适应性试验来揭示耐药结核分枝杆菌中rpsL和gyrA不同突变之间的相互作用，随后分析来自四川地区的213株STR-FLQ双重耐药临床结核分枝杆菌分离株中rpsL和gyrA突变组合的频率，还通过来自3056株全球临床结核分枝杆菌分离株的全基因组数据进行了调查。
rpsL中具有K43R和K88R突变的菌株与其敏感祖先相比，相对适应性没有差异，而K43N、K43M、K43T和K88E的相对适应性显著较低（<0.05）。对于FLQ耐药突变体，所有突变类型的相对适应性均无差异。在STR-FLQ双重耐药结核分枝杆菌菌株中，rpsL中具有K43N/M/T和K88E而非K43R和K88R突变的菌株检测到较低的适应性。在携带rpsL和gyrA双重突变的分离株中，最常见的两种组合突变类型是K43R/D94G（n = 37）和K43R/A90V（n = 24），前者在体外试验和临床调查中都是最常见的。
我们的结果表明，rpsL和gyrA突变之间的相互作用影响STR-FLQ双重耐药结核分枝杆菌的适应性代价以及临床结核分枝杆菌分离株中突变组合的偏好。
