Characterization of the Orphan Cytochrome P450 CYP135B1 from <i>Mycobacterium tuberculosis</i>: Involvement in Metabolism but Not in the Antibacterial Activity of the Antitubercular Drug SQ109
The rise of multidrug-resistant tuberculosis (TB) has increased the need for new antitubercular (anti-TB) drugs and the identification of novel drug targets. One promising target is <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) cytochrome P450 enzymes (P450s). This study focuses on the characterization of CYP135B1, a prevalent <i>Mtb</i> P450. Using a combination of microbiology, genomics, bioinformatics, docking, spectroscopy, and mass spectrometry, researchers successfully expressed, purified, and characterized CYP135B1. A 3D model was built with AlphaFold 3. The enzyme displayed typical features of P450 proteins and showed strong binding to imidazole derivatives. Notably, CYP135B1 metabolized the anti-TB drug SQ109 by inserting oxygen into its geranyl moiety in a manner distinct from CYP124A1. However, genetic studies using a ΔCYP135B1 mutant strain revealed that CYP135B1 is not required for SQ109's antibacterial activity, as its deletion did not affect drug efficacy despite CYP135B1 metabolizes SQ109.
Authors
- Olivier Poch (ORCID: https://orcid.org/0000-0002-7134-3217)
- Gilles Clodic
- Claudine Mayer (ORCID: https://orcid.org/0000-0002-6854-5846)
- Elodie Sadowski (ORCID: https://orcid.org/0000-0002-3021-1672)
- Lucrèce Mathéron
- Emmanuelle Sachon (ORCID: https://orcid.org/0000-0002-2271-8924)
- Cédric Pionneau (ORCID: https://orcid.org/0000-0001-6270-7421)
- Romain Veyron‐Churlet (ORCID: https://orcid.org/0000-0001-6902-5917)
- Nicolas Pietrancosta (ORCID: https://orcid.org/0000-0002-9934-7818)
- Alexandra Aubry (ORCID: https://orcid.org/0000-0003-4230-4793)
- Jean-Luc Boucher
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Université de Lille (FR)
- Institut Pasteur de Lille (FR)
- Sorbonne Université (FR)
- Center for Infection and Immunity of Lille (FR)
- École Normale Supérieure (BI)
- Institut de Biologie Paris-Seine (FR)
- Laboratoire National de Référence (MA)
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (FR)
- Centre d'Immunologie et des Maladies Infectieuses (FR)
- Institut Parisien de Chimie Moléculaire (FR)
- Hôpital Charles-Foix (FR)
- Laboratoire des Biomolécules (FR)
- Neurosciences Paris-Seine (FR)
- Laboratoire Médiations (FR)
- Université de Strasbourg (FR)
Publication Details
- Journal
- ACS Infectious Diseases
- Published
- 2025-04-03
- DOI
- https://doi.org/10.1021/acsinfecdis.4c00893
- Primary Topic
- Pharmacogenetics and Drug Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Agence Nationale de la Recherche
- Centre National de la Recherche Scientifique