Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach.
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Authors
Thomas, Sherine E
Curran, Amy
Brown, Karen P
Belardinelli, Juan M
Whitehouse, Andrew J
Sangan, Jaspar
Floto, R Andres
Blundell, Tom L
Publication Date
2022-02-11Journal Title
ACS Infect Dis
ISSN
2373-8227
Publisher
American Chemical Society (ACS)
Number
acsinfecdis.1c00432
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Charoensutthivarakul, S., Thomas, S. E., Curran, A., Brown, K. P., Belardinelli, J. M., Whitehouse, A. J., Acebrón-García-de-Eulate, M., et al. (2022). Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach.. ACS Infect Dis, (acsinfecdis.1c00432) https://doi.org/10.1021/acsinfecdis.1c00432
Abstract
Mycobacterium abscessus (Mab) has emerged as a challenging threat to individuals with cystic fibrosis. Infections caused by this pathogen are often impossible to treat due to the intrinsic antibiotic resistance leading to lung malfunction and eventually death. Therefore, there is an urgent need to develop new drugs against novel targets in Mab to overcome drug resistance and subsequent treatment failure. In this study, SAICAR synthetase (PurC) from Mab was identified as a promising target for novel antibiotics. An in-house fragment library screen and a high-throughput X-ray crystallographic screen of diverse fragment libraries were explored to provide crucial starting points for fragment elaboration. A series of compounds developed from fragment growing and merging strategies, guided by crystallographic information and careful hit-to-lead optimization, have achieved potent nanomolar binding affinity against the enzyme. Some compounds also show a promising inhibitory effect against Mab and Mtb. This work utilizes a fragment-based design and demonstrates for the first time the potential to develop inhibitors against PurC from Mab.
Sponsorship
Wellcome Trust (200814/Z/16/Z)
Identifiers
External DOI: https://doi.org/10.1021/acsinfecdis.1c00432
This record's URL: https://www.repository.cam.ac.uk/handle/1810/332899
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