Improved antibacterial activity of 1,3,4-oxadiazole-based compounds that restrict Staphylococcus aureus Growth independent of LtaS function
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Author(s)
Type
Journal Article
Abstract
The lipoteichoic acid (LTA) biosynthesis pathway has emerged as a promising antimicrobial therapeutic target. Previous studies identified the 1,3,4 oxadiazole compound 1771 as an LTA inhibitor with activity against Gram-positive pathogens. We have succeeded in making six 1771 derivatives and, through subsequent hit validation, identified the incorporation of a pentafluorosulfanyl substituent as central in enhancing activity. Our newly described derivative, compound 13, showed a 16- to 32-fold increase in activity compared to 1771 when tested against a cohort of multidrug-resistant Staphylococcus aureus strains while simultaneously exhibiting an improved toxicity profile against mammalian cells. Molecular techniques were employed in which the assumed target, lipoteichoic acid synthase (LtaS), was both deleted and overexpressed. Neither deletion nor overexpression of LtaS altered 1771 or compound 13 susceptibility; however, overexpression of LtaS increased the MIC of Congo red, a previously identified LtaS inhibitor. These data were further supported by comparing the docking poses of 1771 and derivatives in the LtaS active site, which indicated the possibility of an additional target(s). Finally, we show that both 1771 and compound 13 have activity that is independent of LtaS, extending to cover Gram-negative species if the outer membrane is first permeabilized, challenging the classification that these compounds are strict LtaS inhibitors.
Date Issued
2023-11-10
Date Acceptance
2023-10-01
Citation
ACS Infectious Diseases, 2023, 9 (11), pp.2141-2159
ISSN
2373-8227
Publisher
American Chemical Society (ACS)
Start Page
2141
End Page
2159
Journal / Book Title
ACS Infectious Diseases
Volume
9
Issue
11
Copyright Statement
© 2023 The Authors. Published by American Chemical Society This article is licensed under CC-BY 4.0
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Publication Status
Published
Date Publish Online
2023-10-13