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Development of inhibitors of SAICAR synthetase (PurC) from Mycobacterium abscessus using a fragment-based approach

DOI: 10.1021/acsinfecdis.1c00432 DOI Help

Authors: Sitthivut Charoensutthivarakul (University of Cambridge; Mahidol University) , Sherine E. Thomas (University of Cambridge) , Amy Curran (University of Cambridge) , Karen P. Brown (University of Cambridge; Royal Papworth Hospital) , Juan M. Belardinelli (Colorado State University) , Andrew J. Whitehouse (University of Cambridge) , Marta Acebron-Garcia-De-Eulate (University of Cambridge) , Jaspar Sangan (University of Cambridge; Cambridge Centre for Lung Infection) , Subramanian G. Gramani (University of Cambridge) , Mary Jackson (Colorado State University) , Vitor Mendes (University of Cambridge) , R. Andres Floto (University of Cambridge; Cambridge Centre for Lung Infection) , Tom L. Blundell (University of Cambridge) , Anthony G. Coyne (University of Cambridge) , Chris Abell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: January 2022
Diamond Proposal Number(s): 9537 , 14043 , 18548

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.

Journal Keywords: structure-guided; fragment-based drug discovery; Mycobacterium abscessus; cystic fibrosis; PurC; SAICAR synthetase

Diamond Keywords: Cystic Fibrosis; Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Diamond Offline Facilities: XChem
Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 19/01/2022 08:28

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX) Fragment Screening