Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors

Wezen, Xavier Chee, Chandran, Aneesh, Eapen, Rohan Sakariah, Waters, Elaine, Bricio-Moreno, Laura, Tosi, Tommaso, Dolan, Stephen, Millership, Charlotte, Kadioglu, Aras ORCID: 0000-0003-1137-6321, Grundling, Angelika
et al (show 3 more authors) (2022) Structure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 62 (10). pp. 2586-2599.

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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 <b>1771</b>" 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 <b>1771</b> 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 <b>1771</b>, namely, compound <b>4</b> which showed greater affinity for binding to eLtaS than compound <b>1771</b> in biophysical assays. Compound <b>4</b> reduced LTA production in <i>S. aureus</i> dose-dependently, induced aberrant morphology as seen for LTA-deficient bacteria, and significantly reduced bacteria titers in the lung of mice infected with <i>S. aureus</i>. 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 <i>S. aureus</i>. 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.

Item Type: Article
Uncontrolled Keywords: Animals, Mice, Staphylococcus aureus, Lipopolysaccharides, Teichoic Acids, Methicillin-Resistant Staphylococcus aureus, Molecular Docking Simulation
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User: Symplectic Admin
Date Deposited: 19 Jul 2022 12:50
Last Modified: 27 Nov 2023 09:08
DOI: 10.1021/acs.jcim.2c00300
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