Structure-based discovery of lipoteichoic acid synthase inhibitors.

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Title: Structure-based discovery of lipoteichoic acid synthase inhibitors.
Authors: Chee Wezen, X
Chandran, A
Eapen, RS
Waters, E
Bricio-Moreno, L
Tosi, T
Dolan, S
Millership, C
Kadioglu, A
Gründling, A
Itzhaki, LS
Welch, M
Rahman, T
Item Type: Journal Article
Abstract: Lipoteichoic acid synthase (LtaS) is a key enzyme for the cell wall biosynthesis of Gram-positive bacteria. Gram-positive bacteria that lack lipoteichoic acid (LTA) exhibit impaired cell division and growth defects. Thus, LtaS appears to be an attractive antimicrobial target. The pharmacology around LtaS remains largely unexplored with only two small-molecule LtaS inhibitors reported, namely "compound 1771" and the Congo red dye. Structure-based drug discovery efforts against LtaS remain unattempted due to the lack of an inhibitor-bound structure of LtaS. To address this, we combined the use of a molecular docking technique with molecular dynamics (MD) simulations to model a plausible binding mode of compound 1771 to the extracellular catalytic domain of LtaS (eLtaS). The model was validated using alanine mutagenesis studies combined with isothermal titration calorimetry. Additionally, lead optimization driven by our computational model resulted in an improved version of compound 1771, namely, compound 4 which showed greater affinity for binding to eLtaS than compound 1771 in biophysical assays. Compound 4 reduced LTA production in S. aureus dose-dependently, induced aberrant morphology as seen for LTA-deficient bacteria, and significantly reduced bacteria titers in the lung of mice infected with S. aureus. Analysis of our MD simulation trajectories revealed the possible formation of a transient cryptic pocket in eLtaS. Virtual screening (VS) against the cryptic pocket led to the identification of a new class of inhibitors that could potentiate β-lactams against methicillin-resistant S. aureus. Our overall workflow and data should encourage further drug design campaign against LtaS. Finally, our work reinforces the importance of considering protein conformational flexibility to a successful VS endeavor.
Issue Date: 23-May-2022
Date of Acceptance: 1-May-2022
DOI: 10.1021/acs.jcim.2c00300
ISSN: 1549-9596
Publisher: American Chemical Society
Start Page: 2586
End Page: 2599
Journal / Book Title: Journal of Chemical Information and Modeling
Volume: 62
Issue: 10
Copyright Statement: © 2022 The Authors. Published by American Chemical Society
Sponsor/Funder: Wellcome Trust
Medical Research Council (MRC)
Funder's Grant Number: 100289/Z/12/Z
Keywords: Animals
Methicillin-Resistant Staphylococcus aureus
Molecular Docking Simulation
Staphylococcus aureus
Teichoic Acids
Staphylococcus aureus
Teichoic Acids
Methicillin-Resistant Staphylococcus aureus
Molecular Docking Simulation
Methicillin-Resistant Staphylococcus aureus
Molecular Docking Simulation
Staphylococcus aureus
Teichoic Acids
Medicinal & Biomolecular Chemistry
0304 Medicinal and Biomolecular Chemistry
0307 Theoretical and Computational Chemistry
0802 Computation Theory and Mathematics
Publication Status: Published
Conference Place: United States
Online Publication Date: 2022-05-09
Appears in Collections:Department of Infectious Diseases
Faculty of Medicine

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