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

  • ACS Infect Dis. 2025 Apr 11;11(4):986-997. doi: 10.1021/acsinfecdis.4c01030.
Deborah Recchia  1 ,  Giovanni Stelitano  1 ,  Anna Egorova  2 ,  Gherard Batisti Biffignandi  1 ,  Karin Savková  3 ,  Radka Kafková  3 ,  Stanislav Huszár  3 ,  Antonio Marino Cerrato  1 ,  Richard A Slayden  4 ,  Jason E Cummings  4 ,  Nicholas Whittel  4 ,  Allison A Bauman  5 ,  Gregory T Robertson  4 ,  Laura Rank  6 ,  Fabio Urbina  6 ,  Thomas R Lane  6 ,  Sean Ekins  6 ,  Olga Riabova  2 ,  Elena Kazakova  2 ,  Katarína Mikušová  3 ,  Davide Sassera  1  7 ,  Giulia Degiacomi  1 ,  Laurent Robert Chiarelli  1 ,  Vadim Makarov  2 ,  Maria Rosalia Pasca  1  7
Affiliations
  • 1. Department of Biology and Biotechnology "Lazzaro Spallanzani,", University of Pavia, 27100 Pavia, Italy.
  • 2. Research Centre of Biotechnology RAS, Moscow 119071, Russia.
  • 3. Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, 814 99 Bratislava, Slovakia.
  • 4. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, USA.
  • 5. Colorado State University, 1682 Campus Delivery, 200 West Lake Street, Fort Collins, Colorado 80523-1782, United States.
  • 6. Collaborations Pharmaceuticals, Inc., Raleigh, North Carolina 27606, United States.
  • 7. Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
PMID: 40111403 DOI: 10.1021/acsinfecdis.4c01030
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.

Keywords
Rv3406; antitubercular drugs; drug inactivation; tuberculosis.
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