Title :

Structural Characterization of Mycobacterium abscessus Phosphopantetheine Adenylyl Transferase Ligand Interactions: Implications for Fragment-Based Drug Design

Author(s) :

Thomas, Sherine Elizabeth [Auteur]
Department of Biochemistry, University of Cambridge
Mccarthy, William J. [Auteur]
University of Cambridge [UK] [CAM]
El Bakali, Jamal [Auteur]
University of Cambridge [UK] [CAM]
Brown, Karen P. [Auteur]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Kim, So Yeon [Auteur]
Department of Biochemistry, University of Cambridge
Blaszczyk, Michal [Auteur]
Department of Biochemistry, University of Cambridge
Mendes, Vitor [Auteur]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Department of Biochemistry, University of Cambridge
Abell, Chris [Auteur]
University of Cambridge [UK] [CAM]
Floto, R. Andres [Auteur]
MRC Laboratory of Molecular Biology [Cambridge, UK] [LMB]
Coyne, Anthony G. [Auteur]
University of Cambridge [UK] [CAM]
Blundell, Tom L. [Auteur]
Department of Biochemistry, University of Cambridge

Journal title :

Frontiers in Molecular Biosciences

Abbreviated title :

Front Mol Biosci

Volume number :

9

Pages :

880432

Publisher :

Frontiers Media

Publication date :

2022-05-30

ISSN :

2296-889X

English keyword(s) :

antibiotics
fragment-based
drug discovery
PPAT
CoaD
Coenzyme A pathway
Mycobacterium tuberculosis
Mycobacterium abscessus

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Anti-microbial resistance is a rising global healthcare concern that needs urgent attention as growing number of infections become difficult to treat with the currently available antibiotics. This is particularly true for ...
Show more >Anti-microbial resistance is a rising global healthcare concern that needs urgent attention as growing number of infections become difficult to treat with the currently available antibiotics. This is particularly true for mycobacterial infections like tuberculosis and leprosy and those with emerging opportunistic pathogens such as Mycobacterium abscessus, where multi-drug resistance leads to increased healthcare cost and mortality. M. abscessus is a highly drug-resistant non-tuberculous mycobacterium which causes life-threatening infections in people with chronic lung conditions such as cystic fibrosis. In this study, we explore M. abscessus phosphopantetheine adenylyl transferase (PPAT), an enzyme involved in the biosynthesis of Coenzyme A, as a target for the development of new antibiotics. We provide structural insights into substrate and feedback inhibitor binding modes of M. abscessus PPAT, thereby setting the basis for further chemical exploration of the enzyme. We then utilize a multi-dimensional fragment screening approach involving biophysical and structural analysis, followed by evaluation of compounds from a previous fragment-based drug discovery campaign against M. tuberculosis PPAT ortholog. This allowed the identification of an early-stage lead molecule exhibiting low micro molar affinity against M. abscessus PPAT (Kd 3.2 ± 0.8 µM) and potential new ways to design inhibitors against this enzyme. The resulting crystal structures reveal striking conformational changes and closure of solvent channel of M. abscessus PPAT hexamer providing novel strategies of inhibition. The study thus validates the ligandability of M. abscessus PPAT as an antibiotic target and identifies crucial starting points for structure-guided drug discovery against this bacterium.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Autres travaux scientifiques

Submission date :

2024-01-16T01:06:03Z
2025-02-18T14:55:41Z