Publication
Title
Expanding the squaramide library as mycobacterial ATP synthase inhibitors : innovative synthetic pathway and biological evaluation
Author
Abstract
Mycobacterial ATP synthase is a validated therapeutic target for combating drug-resistant tuberculosis. Inhibition of this enzyme has been featured as an efficient strategy for the development of new antimycobacterial agents against drug-resistant pathogens. In this study, we synthesised and explored two distinct series of squaric acid analogues designed to inhibit mycobacterial ATP synthase. Among the extensive array of compounds investigated, members of the phenyl-substituted sub-library emerged as primary hits. To gain deeper insights into their mechanisms of action, we conducted advanced biological studies, focusing on the compounds displaying a direct binding of a nitrogen heteroatom to the phenyl ring, resulting in the highest potency. Our investigations into spontaneous mutants led to the validation of a single point mutation within the atpB gene (Rv1304), responsible for encoding the ATP synthase subunit a. This genetic alteration sheds light on the molecular basis of resistance to squaramides. Furthermore, we explored the possibility of synergy between squaramides and the reference drug clofazimine using a checkerboard assay, highlighting the promising avenue for enhancing the effectiveness of existing treatments through combined therapeutic approaches. This study contributes to the expansion of investigating squaramides as promising drug candidates in the ongoing battle against drug-resistant tuberculosis.
Language
English
Source (journal)
Bioorganic and medicinal chemistry. - Oxford
Publication
Oxford : 2023
ISSN
0968-0896
DOI
10.1016/J.BMC.2023.117504
Volume/pages
95 (2023) , p. 1-18
Article Reference
117504
ISI
001094614900001
Pubmed ID
37871508
Medium
E-only publicatie
Full text (Publisher's DOI)
Full text (open access)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
Development of a comprehensive platform for targeting redox homeostasis in Mycobacterium tuberculosis.
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 22.10.2023
Last edited 25.04.2024
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