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

Autor:	Charoensutthivarakul S; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.; School of Bioinnovation and Bio-based Product Intelligence, Faculty of Science, Mahidol University, Bangkok 10400, Thailand., Thomas SE; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, United Kingdom., Curran A; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom., Brown KP; Molecular Immunity Unit, Department of Medicine, MRC Laboratory of Molecular Biology, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge CB23 3RE, United Kingdom., Belardinelli JM; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, United States., Whitehouse AJ; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom., Acebrón-García-de-Eulate M; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, United Kingdom., Sangan J; Molecular Immunity Unit, Department of Medicine, MRC Laboratory of Molecular Biology, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge CB23 3RE, United Kingdom., Gramani SG; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom., Jackson M; Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523-1682, United States., Mendes V; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, United Kingdom., Floto RA; Molecular Immunity Unit, Department of Medicine, MRC Laboratory of Molecular Biology, University of Cambridge, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, United Kingdom.; Cambridge Centre for Lung Infection, Royal Papworth Hospital, Cambridge CB23 3RE, United Kingdom., Blundell TL; Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, United Kingdom., Coyne AG; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom., Abell C; Yusuf Hamied Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom.
Jazyk:	angličtina
Zdroj:	ACS infectious diseases [ACS Infect Dis] 2022 Feb 11; Vol. 8 (2), pp. 296-309. Date of Electronic Publication: 2022 Jan 17.
DOI:	10.1021/acsinfecdis.1c00432
Abstrakt:	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 .
Databáze:	MEDLINE
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