Synthesis, molecular docking and antibacterial activity of an oxadiazole-based lipoteichoic acid inhibitor and its metabolites

Serpi, Michaela ORCID: https://orcid.org/0000-0002-6162-7910, Pertusati, Fabrizio ORCID: https://orcid.org/0000-0003-4532-9101, Morozzi, Chiara, Novelli, Giulia, Giannantonio, Daniele, Duggan, Katrina, Vittorio, Serena, Fallis, Ian A. ORCID: https://orcid.org/0000-0001-7361-0182, De Luca, Laura and Williams, David ORCID: https://orcid.org/0000-0002-7351-5131 2023. Synthesis, molecular docking and antibacterial activity of an oxadiazole-based lipoteichoic acid inhibitor and its metabolites. Journal of Molecular Structure 1278 , 134977. 10.1016/j.molstruc.2023.134977

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Abstract

Amongst drug resistant Gram-positive bacteria, Staphylococcus aureus is a pathogen of great concern as it is the leading cause of life-threatening nosocomial and community acquired infections which are often associated with implanted medical devices. The biosynthesis of lipotheicoic acid (LTA) by S. aureus has been recognized as a promising antibacterial target, owing its critical role in the growth and survival of Gram-positive bacteria. Here we report for the first time the chemical synthesis and characterisation of an oxadiazole based compound (1771), previously described as an inhibitor of LTA biosynthesis by targeting Lta synthase enzyme (LtaS). To investigate its controversial mode of action, we also performed molecular docking studies, which indicated that 1771 behaves as a competitive inhibitor against LtaS. We also synthesised and evaluated the antimicrobial activity of 1771 metabolites which we have identified from its decomposition in mouse serum, proving that the biological activity was caused by intact 1771.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Dentistry Chemistry
Publisher:	Elsevier
ISSN:	0022-2860
Funders:	Wellcome Trust
Date of First Compliant Deposit:	18 January 2023
Date of Acceptance:	14 January 2023
Last Modified:	06 Dec 2023 02:06
URI:	https://orca.cardiff.ac.uk/id/eprint/156073

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