Structural Characterization of Mycobacterium abscessus Phosphopantetheine Adenylyl Transferase Ligand Interactions: Implications for Fragment-Based Drug Design
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...
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Published in | Frontiers in molecular biosciences Vol. 9; p. 880432 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Switzerland
Frontiers Media S.A
30.05.2022
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Subjects | |
Online Access | Get full text |
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Summary: | 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
, where multi-drug resistance leads to increased healthcare cost and mortality.
is a highly drug-resistant non-tuberculous
which causes life-threatening infections in people with chronic lung conditions such as cystic fibrosis. In this study, we explore
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
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
PPAT ortholog. This allowed the identification of an early-stage lead molecule exhibiting low micro molar affinity against
PPAT (K
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
PPAT hexamer providing novel strategies of inhibition. The study thus validates the ligandability of
PPAT as an antibiotic target and identifies crucial starting points for structure-guided drug discovery against this bacterium. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Structural Biology, a section of the journal Frontiers in Molecular Biosciences Anshu Bhardwaj, Institute of Microbial Technology (CSIR), India Edited by: Marco Nardini, University of Milan, Italy Present addresses: Sherine E. Thomas, Department of Pathology, University of Cambridge, Cambridge, United Kingdom William J. McCarthy, The Francis Crick Institute, London, United Kingdom Jamal El Bakali, Inserm, CHU Lille, UMR-S 1172-LiNC-Lille Neuroscience & Cognition, University of Lille, Lille, France Michal Blaszczyk, Department of Medicine, Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, United Kingdom Reviewed by: Ramandeep Singh, Translational Health Science and Technology Institute (THSTI), India |
ISSN: | 2296-889X 2296-889X |
DOI: | 10.3389/fmolb.2022.880432 |