TY - JOUR T1 - Hydroxylation of antitubercular drug candidate, SQ109, by mycobacterial cytochrome P450 JF - bioRxiv DO - 10.1101/2020.08.27.269936 SP - 2020.08.27.269936 AU - Sergey Bukhdruker AU - Tatsiana Varaksa AU - Irina Grabovec AU - Egor Marin AU - Polina Shabunya AU - Maria Kadukova AU - Sergei Grudinin AU - Anton Kavaleuski AU - Anastasiia Gusach AU - Andrei Gilep AU - Valentin Borshchevskiy AU - Natallia Strushkevich Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/08/27/2020.08.27.269936.abstract N2 - Spreading of the multidrug-resistant (MDR) strains of the deadliest pathogen Mycobacterium tuberculosis (Mtb) generates the need for new effective drugs. SQ109 showed activity against resistant Mtb and already advanced to Phase II/III clinical trials. Fast SQ109 degradation is attributed to the human liver Cytochrome P450s (CYPs). However, no information is available about interactions of the drug with Mtb CYPs. Here, we show that Mtb CYP124, previously assigned as a methyl-branched lipid monooxygenase, binds and hydroxylates SQ109 in vitro. A 1.25 Å-resolution crystal structure of the CYP124–SQ109 complex unambiguously shows two conformations of the drug, both positioned for hydroxylation of the ω-methyl group in the trans position. The hydroxylated SQ109 presumably forms stabilizing H-bonds with its target, the Mycobacterial membrane protein Large 3 (MmpL3). We anticipate that Mtb CYPs could function as analogs of drug-metabolizing human CYPs affecting pharmacokinetics and pharmacodynamics of antitubercular (anti-TB) drugs.Competing Interest StatementAndrei Gilep is an employee of MT-Medicals LLC. The other authors declare no competing interests. ER -