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Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Chandran, Aneesh 
Eapen, Rohan Sakariah 
Waters, Elaine 
Bricio-Moreno, Laura 

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.

Description

Funder: Cambridge Trust


Funder: Islamic Development Bank


Funder: AstraZeneca

Keywords

Animals, Lipopolysaccharides, Methicillin-Resistant Staphylococcus aureus, Mice, Molecular Docking Simulation, Staphylococcus aureus, Teichoic Acids

Journal Title

J Chem Inf Model

Conference Name

Journal ISSN

1549-9596
1549-960X

Volume Title

62

Publisher

American Chemical Society (ACS)
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/M019411/1)