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ACS infectious diseases
11 10, 2023;9 (11): 2141-2159.

Improved Antibacterial Activity of 1,3,4-Oxadiazole-Based Compounds That Restrict Growth Independent of LtaS Function.

Edward J A Douglas, Brandon Marshall, Arwa Alghamadi, Erin A Joseph, Se��na Duggan, Serena Vittorio, Laura De Luca, Michaela Serpi, Maisem Laabei
Author Information
  1. Edward J A Douglas: Department of Life Sciences, University of Bath, Bath BA2 7AY, U.K.
  2. Brandon Marshall: School of Chemistry, Cardiff University, Cardiff CF10 3AT, Wales, U.K.
  3. Arwa Alghamadi: School of Chemistry, Cardiff University, Cardiff CF10 3AT, Wales, U.K.
  4. Erin A Joseph: School of Chemistry, Cardiff University, Cardiff CF10 3AT, Wales, U.K.
  5. Se��na Duggan: Medical Research Council Centre for Medical Mycology at the University of Exeter, University of Exeter, Exeter EX4 4DQ, U.K. ORCID
  6. Serena Vittorio: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98125, Italy. ORCID
  7. Laura De Luca: Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Messina I-98125, Italy.
  8. Michaela Serpi: School of Chemistry, Cardiff University, Cardiff CF10 3AT, Wales, U.K. ORCID
  9. Maisem Laabei: Department of Life Sciences, University of Bath, Bath BA2 7AY, U.K. ORCID
PMID: 37828912 DOI: 10.1021/acsinfecdis.3c00250

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 , showed a 16- to 32-fold increase in activity compared to 1771 when tested against a cohort of multidrug-resistant 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 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 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.

Keywords

1,3,4 oxadiazole Staphylococcus aureus antimicrobial resistance drug discovery lipoteichoic acid inhibitors

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Grants

  1. MR/V033417/1/Medical Research Council
  2. /Department of Health

MeSH Term

Animals
Anti-Bacterial Agents
Mammals
Methicillin-Resistant Staphylococcus aureus
Oxadiazoles
Staphylococcal Infections
Staphylococcus aureus

Chemicals

1,3,4-oxadiazole
Anti-Bacterial Agents
lipoteichoic acid
Oxadiazoles
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 7

Word Cloud

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