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Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Charoensutthivarakul, Sitthivut  ORCID logo  https://orcid.org/0000-0002-4447-3438
Thomas, Sherine E 
Curran, Amy 
Brown, Karen P 
Belardinelli, Juan M 

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.

Description

Keywords

Mycobacterium abscessus, PurC, SAICAR synthetase, cystic fibrosis, fragment-based drug discovery, structure-guided, Anti-Bacterial Agents, Crystallography, X-Ray, Humans, Mycobacterium abscessus, Peptide Synthases

Journal Title

ACS Infect Dis

Conference Name

Journal ISSN

2373-8227
2373-8227

Volume Title

Publisher

American Chemical Society (ACS)
Sponsorship
Wellcome Trust (200814/Z/16/Z)
Wellcome Trust (107032/B/15/Z)