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Development of Inhibitors of SAICAR Synthetase (PurC) from Mycobacterium abscessus Using a Fragment-Based Approach
Sitthivut Charoensutthivarakul1,2, Sherine E Thomas3, Amy Curran1
1Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
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.
Insights
New antibiotics targeting SAICAR synthetase (PurC) show promise against Mycobacterium abscessus (Mab), a difficult-to-treat pathogen common in cystic fibrosis patients. This research offers hope for overcoming drug resistance in Mab infections.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Mycobacterium abscessus (Mab) infections pose a significant challenge, particularly for cystic fibrosis patients, due to inherent antibiotic resistance.
- The limited treatment options for Mab infections necessitate the development of novel drugs targeting new pathways.
- Drug resistance in Mab leads to severe lung complications and increased mortality.
Purpose of the Study:
- To identify and validate novel drug targets in Mycobacterium abscessus.
- To develop potent inhibitors against SAICAR synthetase (PurC) as a potential therapeutic strategy for Mab infections.
- To explore fragment-based drug design approaches for generating novel antibiotic leads.
Main Methods:
- Screening of in-house and diverse fragment libraries using high-throughput X-ray crystallography.
- Fragment growing and merging strategies guided by crystallographic data.
- Hit-to-lead optimization to achieve potent binding affinity and inhibitory activity.
Main Results:
- SAICAR synthetase (PurC) was identified as a promising drug target in Mycobacterium abscessus.
- A series of compounds were developed with potent nanomolar binding affinity against PurC.
- Some developed compounds demonstrated promising inhibitory effects against both Mab and Mycobacterium tuberculosis (Mtb).
Conclusions:
- Fragment-based design is a viable strategy for developing novel inhibitors against PurC in Mab.
- This study presents the first demonstration of potential PurC inhibitors for treating Mab infections.
- The findings offer a new avenue for combating antibiotic-resistant Mycobacterium abscessus.
