Characterization of the Orphan Cytochrome P450 CYP135B1 from Mycobacterium tuberculosis: Involvement in Metabolism but Not in the Antibacterial Activity of the Antitubercular Drug SQ109.

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL ACS Infectious Diseases Pub Date : 2025-04-11 Epub Date: 2025-04-02 DOI:10.1021/acsinfecdis.4c00893

Elodie Sadowski, Nicolas Pietrancosta, Romain Veyron-Churlet, Jean-Luc Boucher, Cédric Pionneau, Gilles Clodic, Lucrèce Matheron, Olivier Poch, Claudine Mayer, Emmanuelle Sachon, Alexandra Aubry

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Abstract

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 Mycobacterium tuberculosis (Mtb) cytochrome P450 enzymes (P450s). This study focuses on the characterization of CYP135B1, a prevalent Mtb 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.

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结核分枝杆菌孤儿细胞色素P450 CYP135B1的特征：参与抗结核药物SQ109的代谢而非抗菌活性

耐多药结核病（TB）的增加增加了对新的抗结核药物（anti-TB）和确定新的药物靶点的需求。一个有希望的靶标是结核分枝杆菌（Mtb）细胞色素P450酶（P450）。本研究的重点是CYP135B1的表征，这是一种常见的Mtb P450。结合微生物学、基因组学、生物信息学、对接、光谱学和质谱，研究人员成功表达、纯化和表征了CYP135B1。利用AlphaFold 3建立三维模型。该酶表现出P450蛋白的典型特征，并与咪唑衍生物有较强的结合。值得注意的是，CYP135B1通过将氧插入其香叶基片段来代谢抗结核药物SQ109，其方式与CYP124A1不同。然而，利用ΔCYP135B1突变株进行的遗传学研究表明，CYP135B1不是SQ109抗菌活性所必需的，尽管CYP135B1代谢了SQ109，但它的缺失并不影响药效。

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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.

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