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

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.