Interaction between and mutations affects the fitness and dual resistance of clinical isolates against streptomycin and fluoroquinolones.

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 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.

RESULTS

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.

CONCLUSION

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.