Mycobacteriumabscessus CYP123 is a steroid hydroxylase with an implication in host infection

Mycobacterium abscessus (Mab, MAB) poses a rising health threat worldwide. Infections occur in hospital settings, affecting immunocompromised and immunocompetent patients alike. Individuals with underlying lung diseases, such as cystic fibrosis and bronchiectasis, are particularly at risk. Mab is intrinsically multidrug resistant to most antibiotics, has high treatment failure to current treatment regimens, and lacks a vaccine. Targeting bacterial metabolism has historically resulted in successful therapies. We discovered that the cytochrome P450 isoform CYP123 encoded by MAB_1216c is required for host infection. To determine the role of CYP123 during host infection, we generated highly active recombinant CYP123 and found CYP123 interactions with steroid hormones, which are key players in host immune response. All tested steroids induced a reverse type I shift when titrated to the enzyme. Their binding affinity was dictated by the presence of hydroxyl groups at certain positions in the steroid scaffold. Metabolism assays with a surrogate redox system revealed that CYP123 is a steroid hydroxylase and can convert 11-deoxycorticosterone and progesterone to a single monohydroxylated product, respectively. Mab infection has been associated with fungal coinfection, and cytochrome P450 enzymes have been shown to interact with azoles. We found that CYP123 binds to various triazole and azole drugs in the low micromolar range. Our results indicate that Mab CYP123 can interfere with host endobiotics with a potential implication in host cell reprogramming and can bind antifungal therapeutics possibly leading to worse polymicrobial infections. CYP123 could emerge as a potential drug target for an orthogonal approach to treating Mab infections. SIGNIFICANCE STATEMENT: Infections with the pathogen Mycobacterium abscessus are on the rise with limited treatment options. The M. abscessus cytochrome P450 CYP123 was identified to play an essential role for host infection. Steroids do not only bind to CYP123 but are also metabolized to monohydroxylated products implicating the potential to interfere with steroidogenesis and immune antagonism by this bacterium.