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dc.contributor.authorChee Wezen, Xavier
dc.contributor.authorChandran, Aneesh
dc.contributor.authorEapen, Rohan Sakariah
dc.contributor.authorWaters, Elaine
dc.contributor.authorBricio-Moreno, Laura
dc.contributor.authorTosi, Tommaso
dc.contributor.authorDolan, Stephen
dc.contributor.authorMillership, Charlotte
dc.contributor.authorKadioglu, Aras
dc.contributor.authorGründling, Angelika
dc.contributor.authorItzhaki, Laura
dc.contributor.authorWelch, Martin
dc.contributor.authorRahman, Md Taufiq
dc.date.accessioned2022-06-10T01:05:48Z
dc.date.available2022-06-10T01:05:48Z
dc.date.issued2022-05-23
dc.identifier.issn1549-9596
dc.identifier.other35533315
dc.identifier.otherPMC9131456
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337971
dc.descriptionFunder: Cambridge Trust
dc.descriptionFunder: Islamic Development Bank
dc.descriptionFunder: AstraZeneca
dc.description.abstractLipoteichoic 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.
dc.languageeng
dc.publisherAmerican Chemical Society (ACS)
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.sourcenlmid: 101230060
dc.sourceessn: 1549-960X
dc.subjectAnimals
dc.subjectMice
dc.subjectStaphylococcus aureus
dc.subjectLipopolysaccharides
dc.subjectTeichoic Acids
dc.subjectMethicillin-Resistant Staphylococcus aureus
dc.subjectMolecular Docking Simulation
dc.titleStructure-Based Discovery of Lipoteichoic Acid Synthase Inhibitors.
dc.typeArticle
dc.date.updated2022-06-10T01:05:48Z
prism.endingPage2599
prism.issueIdentifier10
prism.publicationNameJ Chem Inf Model
prism.startingPage2586
prism.volume62
dc.identifier.doi10.17863/CAM.85377
dcterms.dateAccepted2022-04-22
rioxxterms.versionofrecord10.1021/acs.jcim.2c00300
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidChee Wezen, Xavier [0000-0001-8497-5953]
dc.contributor.orcidItzhaki, Laura [0000-0001-6504-2576]
dc.contributor.orcidWelch, Martin [0000-0003-3646-1733]
dc.contributor.orcidRahman, Md Taufiq [0000-0003-3830-5160]
dc.identifier.eissn1549-960X
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/M019411/1)
cam.issuedOnline2022-05-09


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International