Mycobacterium tuberculosis Sulfate Ester Dioxygenase Rv3406 Is Able to Inactivate the RCB18350 Compound.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL ACS Infectious Diseases Pub Date : 2025-03-20 DOI:10.1021/acsinfecdis.4c01030

Deborah Recchia, Giovanni Stelitano, Anna Egorova, Gherard Batisti Biffignandi, Karin Savková, Radka Kafková, Stanislav Huszár, Antonio Marino Cerrato, Richard A Slayden, Jason E Cummings, Nicholas Whittel, Allison A Bauman, Gregory T Robertson, Laura Rank, Fabio Urbina, Thomas R Lane, Sean Ekins, Olga Riabova, Elena Kazakova, Katarína Mikušová, Davide Sassera, Giulia Degiacomi, Laurent Robert Chiarelli, Vadim Makarov, Maria Rosalia Pasca

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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.

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.