Interaction between rpsL and gyrA mutations affects the fitness and dual resistance of Mycobacterium tuberculosis clinical isolates against streptomycin and fluoroquinolones

Interaction between rpsL and gyrA mutations affects the fitness and dual resistance of Mycobacterium tuberculosis clinical isolates against streptomycin and fluoroquinolones Honghu Sun,1,2,* Jumei Zeng,3,* Song Li,1 Pengkuan Liang,1 Chao Zheng,1 Yong Liu,4 Tao Luo,5 Nalin Rastogi,6 Qun Sun,1 1Key Laboratory of Bio-Resources and Eco-Environment of the Ministry of Education, College of Life Sciences, Sichuan University, 2Chengdu Institutes for Food and Drug Control, Chengdu, Sichuan, People’s Republic of China; 3Department of Infectious Diseases, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; 4Public Health Clinical Center of Chengdu, 5West China College of Preclinical Medicine and Forensic Medicine, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 6WHO Supranational TB Reference Laboratory, Institut Pasteur de la Guadeloupe, Abymes, Guadeloupe, France *These authors contributed equally to this work Background: 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).Materials and methods: We used an in vitro competitive fitness assay to reveal the interactions between different mutations of rpsL and gyrA in drug-resistant Mycobacterium smegmatis, followed by the analysis of the frequency of rpsL and gyrA mutation combinations in 213 STR–FLQ dual-resistant clinical Mycobacterium tuberculosis isolates from Sichuan region, which was also investigated by the whole genome data from 3,056 global clinical M. tuberculosis isolates.Results: The strains with K43R and K88R mutation in rpsL showed no difference in relative fitness compared with their susceptible ancestor, while K43N, K43M, K43T, and K88E exhibited a significantly lower relative fitness (P