Identification of 2-Aryl-Quinolone Inhibitors of Cytochrome bd and Chemical Validation of Combination Strategies for Respiratory Inhibitors against Mycobacterium tuberculosis

Jeffreys, Laura ORCID: https://orcid.org/0000-0002-0607-6116, Ardrey, Alison, Hafiz, Taghreed, Dyer, Lauri-Anne, Warman, Ashley, Mosallam, Nada, Nixon, Gemma, Fisher, Nicholas, Hong, W. David, Leung, Suet C., Aljayyoussi, Ghaith, Bibby, Jaclyn, Almeida, Deepak V., Converse, Paul J., Fotouhi, Nader, Berry, Neil G., Nuermberger, Eric L., Upton, Anna M., O’Neill, Paul M., Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192 and Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595 (2023) 'Identification of 2-Aryl-Quinolone Inhibitors of Cytochrome bd and Chemical Validation of Combination Strategies for Respiratory Inhibitors against Mycobacterium tuberculosis'. ACS Infectious Diseases, Vol 9, Issue 2, pp. 221-238.

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Abstract

Mycobacterium tuberculosis cytochrome bd quinol oxidase (cyt bd), the alternative terminal oxidase of the respiratory chain, has been identified as playing a key role during chronic infection and presents a putative target for the development of novel antitubercular agents. Here, we report confirmation of successful heterologous expression of M. tuberculosis cytochrome bd. The heterologous M. tuberculosis cytochrome bd expression system was used to identify a chemical series of inhibitors based on the 2-aryl-quinolone pharmacophore. Cytochrome bd inhibitors displayed modest efficacy in M. tuberculosis growth suppression assays together with a bacteriostatic phenotype in time-kill curve assays. Significantly, however, inhibitor combinations containing our front-runner cyt bd inhibitor CK-2-63 with either cyt bcc-aa3 inhibitors (e.g., Q203) and/or adenosine triphosphate (ATP) synthase inhibitors (e.g., bedaquiline) displayed enhanced efficacy with respect to the reduction of mycobacterium oxygen consumption, growth suppression, and in vitro sterilization kinetics. In vivo combinations of Q203 and CK-2-63 resulted in a modest lowering of lung burden compared to treatment with Q203 alone. The reduced efficacy in the in vivo experiments compared to in vitro experiments was shown to be a result of high plasma protein binding and a low unbound drug exposure at the target site. While further development is required to improve the tractability of cyt bd inhibitors for clinical evaluation, these data support the approach of using small-molecule inhibitors to target multiple components of the branched respiratory chain of M. tuberculosis as a combination strategy to improve therapeutic and pharmacokinetic/pharmacodynamic (PK/PD) indices related to efficacy.

Item Type:	Article
Subjects:	QU Biochemistry > Cells and Genetics > QU 300 General works QV Pharmacology > QV 38 Drug action. QW Microbiology and Immunology > QW 50 Bacteria (General). Bacteriology. Archaea WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1021/acsinfecdis.2c00283
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	01 Feb 2023 14:17
Last Modified:	05 Nov 2024 11:16
URI:	https://archive.lstmed.ac.uk/id/eprint/21783

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