PT  - JOURNAL ARTICLE
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
TI  - Hydroxylation of antitubercular drug candidate, SQ109, by mycobacterial cytochrome P450
AID  - 10.1101/2020.08.27.269936
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.27.269936
4099  - http://biorxiv.org/content/early/2020/08/27/2020.08.27.269936.short
4100  - http://biorxiv.org/content/early/2020/08/27/2020.08.27.269936.full
AB  - 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.