Among the critical priority pathogens listed by the World Health Organization, Mycobacterium tuberculosis strains resistant to rifampicin present a significant global threat. Consequently, the study of the mechanisms of resistance to new antitubercular drugs and the discovery of new effective molecules are two crucial points in tuberculosis drug discovery. In this study, we discovered a compound named RCB18350, which is active against M. tuberculosis growth and exhibits a minimum inhibitory concentration (MIC) of 1.25 μg/mL. It was also effective against multidrug-resistant isolates. We deeply studied the mechanism of resistance/action of RCB18350 by using several approaches. We found that Rv3406, an iron- and α-ketoglutarate-dependent sulfate ester dioxygenase, is capable of metabolizing the compound into its inactive metabolite. This finding highlights the role of this enzyme in the mechanism of resistance to RCB18350.
Mycobacterium tuberculosis Sulfate Ester Dioxygenase Rv3406 Is Able to Inactivate the RCB18350 Compound.
Recchia D;Stelitano G;Batisti Biffignandi G;Marino Cerrato A;Sassera D;Degiacomi G;Chiarelli LR;Pasca MR
2025-01-01
Abstract
Among the critical priority pathogens listed by the World Health Organization, Mycobacterium tuberculosis strains resistant to rifampicin present a significant global threat. Consequently, the study of the mechanisms of resistance to new antitubercular drugs and the discovery of new effective molecules are two crucial points in tuberculosis drug discovery. In this study, we discovered a compound named RCB18350, which is active against M. tuberculosis growth and exhibits a minimum inhibitory concentration (MIC) of 1.25 μg/mL. It was also effective against multidrug-resistant isolates. We deeply studied the mechanism of resistance/action of RCB18350 by using several approaches. We found that Rv3406, an iron- and α-ketoglutarate-dependent sulfate ester dioxygenase, is capable of metabolizing the compound into its inactive metabolite. This finding highlights the role of this enzyme in the mechanism of resistance to RCB18350.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
