Perchlozone Resistance in Clinical Isolates of Mycobacterium tuberculosis

Abstract

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.

A Review of Antibacterial Candidates with New Modes of Action

“…396,397 EthA is also involved in the bioactivation of the thiourea thiocarlide (isoxyl), and the thiosemicarbazones, thioacetazone and perchlozone. 399,400,403 The spiroisoxazoline alpibectir ( 103) is currently being evaluated in a phase 2 trial (NCT05473195) in combination with ethionamide (104) compared to 104 alone in participants with rifampicin-and isoniazid-susceptible pulmonary TB. Nontraditional Small Molecule MoAs: Compounds of Interest.…”

“…Ethionamide ( 104 ) is a prodrug that is activated by Baeyer–Villiger monooxygenases such as EthA, initiating formation of an adduct with NADH, which inhibits the enoyl acyl carrier protein reductase InhA leading to disruption of mycolic acid biosynthesis and cell death. − However, high concentrations of ethionamide ( 104 ) are usually required, which can lead to side effects, as the expression of ethA is negatively regulated by transcriptional repressor EthR . It was shown that spiroisoxazolines inhibit the repressor EthR, which led to increased levels of EthA and activated ethionamide ( 104 ). , EthA is also involved in the bioactivation of the thiourea thiocarlide (isoxyl), and the thiosemicarbazones, thioacetazone and perchlozone. ,, The spiroisoxazoline alpibectir ( 103 ) is currently being evaluated in a phase 2 trial (NCT05473195) in combination with ethionamide ( 104 ) compared to 104 alone in participants with rifampicin- and isoniazid-susceptible pulmonary TB.…”