<i>Mycobacterium tuberculosis</i> Sulfate Ester Dioxygenase Rv3406 Is Able to Inactivate the RCB18350 Compound
Among the critical priority pathogens listed by the World Health Organization, <i>Mycobacterium tuberculosis</i> 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 <i>M. tuberculosis</i> 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.
Authors
- Vadim Makarov (ORCID: https://orcid.org/0000-0001-8746-2694)
- Gregory T. Robertson (ORCID: https://orcid.org/0000-0001-7157-4034)
- Thomas R. Lane (ORCID: https://orcid.org/0000-0001-9240-4763)
- Gherard Batisti Biffignandi (ORCID: https://orcid.org/0000-0003-3108-6313)
- Giovanni Stelitano (ORCID: https://orcid.org/0000-0002-5219-4770)
- Allison Bauman (ORCID: https://orcid.org/0000-0002-7925-3099)
- Elena Kazakova (ORCID: https://orcid.org/0000-0002-8546-7333)
- Richard A. Slayden (ORCID: https://orcid.org/0000-0001-6857-7277)
- Jason E. Cummings (ORCID: https://orcid.org/0000-0001-6137-9163)
- Karin Savková (ORCID: https://orcid.org/0000-0003-0442-8197)
- Maria Rosalia Pasca (ORCID: https://orcid.org/0000-0002-8906-4937)
- Nicholas Whittel
- Davide Sassera (ORCID: https://orcid.org/0000-0003-0442-5252)
- Deborah Recchia (ORCID: https://orcid.org/0000-0002-2735-5165)
- Laura Rank
- Katarı́na Mikus̃ová (ORCID: https://orcid.org/0000-0002-0100-4877)
- Olga Riabova (ORCID: https://orcid.org/0000-0002-3794-6495)
- Fabio Urbina
- Giulia Degiacomi (ORCID: https://orcid.org/0000-0002-3626-8311)
- Stanislav Huszár (ORCID: https://orcid.org/0000-0001-7463-1532)
- Sean Ekins (ORCID: https://orcid.org/0000-0002-5691-5790)
- Laurent Robert Chiarelli (ORCID: https://orcid.org/0000-0003-0348-9764)
- Anna Egorova (ORCID: https://orcid.org/0000-0002-6708-2421)
- Radka Kafková
- Antonio Marino Cerrato
Institutions
- University of Pavia (IT)
- Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani (IT)
- All-Russian Scientific Research Institute of Food Biotechnology (RU)
- Collaborations Pharmaceuticals (United States) (US)
- Policlinico San Matteo Fondazione (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Comenius University Bratislava (SK)
- Colorado State University (US)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2025-03-20
- DOI
- https://doi.org/10.1021/acsinfecdis.4c01030
- Citations
- 3
- Primary Topic
- Tuberculosis Research and Epidemiology
- Type
- article
- Field-Weighted Citation Impact
- 4.19
Funders
- Agentúra na Podporu Výskumu a Vývoja
- Ministero dell'Università e della Ricerca
- European Regional Development Fund
- National Institute of General Medical Sciences
- National Institute of Environmental Health Sciences
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases