Xanthates: Metabolism by Flavoprotein-Containing Monooxygenases and Antimycobacterial Activity

Area of Science:

• Biochemistry
• Microbiology
• Medicinal Chemistry

Background:

• Ethionamide (ETH) is a crucial drug for treating multidrug-resistant tuberculosis (MDR-TB).
• ETH is a prodrug activated by the mycobacterial enzyme flavin-dependent monooxygenase (EtaA) into its active S-oxide form, inhibiting mycolic acid biosynthesis.
• Identifying new antitubercular agents is critical due to rising drug resistance.

Purpose of the Study:

• To explore xanthates as potential new antitubercular agents.
• To investigate the activation mechanism of xanthates by EtaA and compare it to ETH activation.
• To evaluate the antimycobacterial activity of xanthates against *Mycobacterium tuberculosis*.

Main Methods:

• Purified EtaA enzyme was used to catalyze the oxidation of xanthates and ethionamide (ETH).
• Kinetic parameters (Km, Vmax, kcat) for octyl-xanthate and ETH oxidation by EtaA were determined.
• In vitro antimycobacterial activity of xanthates and ETH against *M. tuberculosis* H37Rv was assessed by determining minimum inhibitory concentrations (MICs).

Main Results:

• Xanthates are oxidized by EtaA to S-oxide metabolites (perxanthates), analogous to ETH activation.
• Octyl-xanthate was oxidized more efficiently by EtaA than ETH, with significantly lower Km and higher kcat values.
• Xanthates demonstrated higher in vitro antimycobacterial activity against *M. tuberculosis* (MIC ~1 µM) compared to ETH (MIC = 12 µM).
• EtaA activity was not inhibited by the reaction products.

Conclusions:

• Xanthates represent a promising new class of antitubercular agents.
• The activation mechanism of xanthates by EtaA is similar to that of ETH, suggesting a viable pathway for drug development.
• Xanthates exhibit superior in vitro efficacy against *M. tuberculosis* compared to ethionamide, offering potential for improved tuberculosis treatment.