Bipolar Distribution of Minimum Inhibitory Concentration of Q203 Across Mycobacterial Species

In this study, we conducted an experimental study to evaluate in vitro susceptibility of Q203 against Mycobacterium tuberculosis, as well as the major pathogenic nontuberculous mycobacterial species. A total of 344 nonduplicate mycobacterium isolates were randomly selected for in vitro susceptibility testing. Overall, Q203 exhibited excellent activity against multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) isolates, whereas it showed high minimum inhibitory concentration (MIC) values for all nontuberculous mycobacteria (NTM) isolates tested. The MIC50 and MIC90 values were both 0.008 mg/L for MDR- and XDR-TB isolates, respectively. In contrast, the MIC50 and MIC90 values of four NTM species were all >16 mg/L. QcrB of M. tuberculosis, a component of the CytBC1 complex of the respiratory chain targeted by Q230, shared 89.7% amino acid sequence identity with Mycobacterium avium QcrB, 87.9% with that of Mycobacterium intracellulare, and 84.0% with that of Mycobacterium fortuitum, whereas with low sequence identity observed in QcrB sequence of Mycobacterium abscessus. Notably, the QcrBs of M. avium and M. intracellulare contained a 10-amino acid insertion in the linker between the eighth and ninth helical region. In conclusion, our data demonstrate the bipolar distribution of Q203 MICs across mycobacterial species. Compared with the high MICs in four clinically relevant mycobacterial species, MDR- and XDR-TB isolates have extremely low MICs, indicating that Q203 is a particularly promising candidate for TB treatment. In addition, the 10-amino acid insertion within QcrBs of M. avium and M. intracellulare may be a plausible explanation for the natural resistance to Q203 among these two species.

Automated summary

This study evaluated the in vitro susceptibility of Q203 against Mycobacterium tuberculosis and major pathogenic nontuberculous mycobacterial species. Q203 demonstrated excellent activity against MDR- and XDR-TB isolates, but exhibited high MIC values for NTM isolates. The presence of a 10-amino acid insertion in QcrBs of M. avium and M. intracellulare may explain their natural resistance to Q203.