Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors.
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Authors
Chandran, Aneesh
Eapen, Rohan Sakariah
Waters, Elaine
Bricio-Moreno, Laura
Tosi, Tommaso
Dolan, Stephen
Millership, Charlotte
Kadioglu, Aras
Gründling, Angelika
Publication Date
2022-05-23Journal Title
J Chem Inf Model
ISSN
1549-9596
Publisher
American Chemical Society
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Chee Wezen, X., Chandran, A., Eapen, R. S., Waters, E., Bricio-Moreno, L., Tosi, T., Dolan, S., et al. (2022). Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors.. J Chem Inf Model https://doi.org/10.1021/acs.jcim.2c00300
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.
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/M019411/1)
Identifiers
External DOI: https://doi.org/10.1021/acs.jcim.2c00300
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336522
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