Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis

Mona Katariya, Matthew Snee, Richard Tunnicliffe, Madeline Kavanagh, Helena Boshoff, Cecilia Amadi, Colin Levy, Andrew Munro, Chris Abell, David Leys, Anthony Coyne, Kirsty McLean

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1 Citation (Scopus)

Abstract

Mycobacterium tuberculosis (Mtb) was responsible for approximately 1.6 million deaths in 2021. With the emergence of extensive drug resistance, novel therapeutic agents are urgently needed, and continued drug discovery efforts required. Host-derived lipids such as cholesterol not only support Mtb growth, but are also suspected to function in immunomodulation, with links to persistence and immune evasion. Mtb cytochrome P450 (CYP) enzymes facilitate key steps in lipid catabolism and thus present potential targets for inhibition. Here we present a series of compounds based on an ethyl 5-(pyridin-4-yl)-1H-indole-2-carboxylate pharmacophore which bind strongly to both Mtb cholesterol oxidases CYP125 and CYP142. Using a structure-guided approach, combined with biophysical characterization, compounds with micromolar range in-cell activity against clinically relevant drug-resistant isolates were obtained. These will incite further development of much-needed additional treatment options and provide routes to probe the role of CYP125 and CYP142 in Mtb pathogenesis.

Original languageEnglish
Article numbere202203868
Number of pages8
JournalChemistry - A European Journal
Volume29
Issue number29
Early online date12 Apr 2023
DOIs
Publication statusPublished - 22 May 2023

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