TY - JOUR
T1 - Structure Based Discovery of Inhibitors of CYP125 and CYP142 from Mycobacterium tuberculosis
AU - Katariya, Mona
AU - Snee, Matthew
AU - Tunnicliffe, Richard
AU - Kavanagh, Madeline
AU - Boshoff, Helena
AU - Amadi, Cecilia
AU - Levy, Colin
AU - Munro, Andrew
AU - Abell, Chris
AU - Leys, David
AU - Coyne, Anthony
AU - McLean, Kirsty
N1 - Funding Information:
The authors would like to than Dr Luiz Pedro de Carvalho and Dr Dimitrios Evangelopolous (Francis Crick Institute), Marina Golovanova for technical support, and Dr Glyn Williams for useful discussions about the biophysics experiments. The authors would also like to thank Diamond Light Source for beamtime (proposal mx17773 and mx24447), and the staff of beamlines I03, I04, I04-1 and I24 for assistance. This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC), and in part by the Division of Intramural Research of the NIAID/NIH. Grant numbers BB/R009775/1 (MK), BB/M011208/1 (MS), BB/R009961/1 and BB/I019227/1 (AWM, DL, and KJM), MMK was also supported by the Cambridge Trust (Cambridge-India Ramanujan Fellowship).
Funding Information:
The authors would like to than Dr Luiz Pedro de Carvalho and Dr Dimitrios Evangelopolous (Francis Crick Institute), Marina Golovanova for technical support, and Dr Glyn Williams for useful discussions about the biophysics experiments. The authors would also like to thank Diamond Light Source for beamtime (proposal mx17773 and mx24447), and the staff of beamlines I03, I04, I04‐1 and I24 for assistance. This work was supported by the Biotechnology and Biological Sciences Research Council (BBSRC), and in part by the Division of Intramural Research of the NIAID/NIH. Grant numbers BB/R009775/1 (MK), BB/M011208/1 (MS), BB/R009961/1 and BB/I019227/1 (AWM, DL, and KJM), MMK was also supported by the Cambridge Trust (Cambridge‐India Ramanujan Fellowship).
Publisher Copyright:
© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.
PY - 2023/5/22
Y1 - 2023/5/22
N2 - 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.
AB - 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.
KW - Cytochrome P450 enzymes
KW - tuberculosis
KW - Structure-activity relationships
KW - Drug design
KW - Inhibitors
KW - inhibitors
KW - structure-activity relationships
KW - drug design
KW - cytochrome P450 enzymes
UR - http://www.scopus.com/inward/record.url?scp=85152365252&partnerID=8YFLogxK
U2 - 10.1002/chem.202203868
DO - 10.1002/chem.202203868
M3 - Article
C2 - 36912255
VL - 29
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 29
M1 - e202203868
ER -
