Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach
Issued Date
2022-02-11
Resource Type
eISSN
23738227
Scopus ID
2-s2.0-85123359611
Pubmed ID
35037462
Journal Title
ACS Infectious Diseases
Volume
8
Issue
2
Start Page
296
End Page
309
Rights Holder(s)
SCOPUS
Bibliographic Citation
ACS Infectious Diseases Vol.8 No.2 (2022) , 296-309
Suggested Citation
Charoensutthivarakul S. Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach. ACS Infectious Diseases Vol.8 No.2 (2022) , 296-309. 309. doi:10.1021/acsinfecdis.1c00432 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/86114
Title
Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach
Author(s)
Other Contributor(s)
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.