The emergence of
drug-resistant tuberculosis forced the development of new drugs and the screening of more effective or less toxic analogues.
Mycolic acid biosynthesis is targeted by several antituberculosis drugs,
isoniazid being one of the most important in
tuberculosis therapy. Recently,
perchlozone, acting on another step in the FAS-II cycle, was officially approved for
tuberculosis treatment in the Russian Federation and was included in the Russian national clinical guidelines. Using the serial dilution method on 7H10
agar plates for
perchlozone and a Sensititre MYCOTB microdilution plate, we analyzed the phenotypic properties of primary clinical isolates of M.
tuberculosis and analyzed the molecular determinants of resistance to
isoniazid,
ethionamide, and
perchlozone. We found a wide variation in the MIC of
perchlozone from 2 to 64 mg/L, correlating with the overall resistance profile: the MIC was higher for MDR and pre-XDR isolates. The cross-resistance between
ethionamide and
perchlozone was driven by mutations in the ethA gene encoding
monooxygenase responsible for the activation of both drugs. The presumably susceptible to
perchlozone and wild-type strains had MICs ranging from 2 to 4 mg/L, and the breakpoint was estimated to be 4 or 8 mg/L. In conclusion, susceptibility to
perchlozone is retained for a part of the MDR strains, as is susceptibility to
ethionamide, providing the possibility of
therapy for such cases based on phenotypic or molecular analysis.