Strathclyde Minor Groove Binders (S-MGBs) with activity against Acanthamoeba castellanii

Leah M.C. McGee, Alemao G. Carpinteyro Sanchez, Marina Perieteanu, Kaveh Eskandari, Yan Bian, Logan Mackie, Louise Young, Rebecca Beveridge, Colin J. Suckling, Craig W. Roberts, Fraser J. Scott*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Acanthamoeba spp. is the causative agent of Acanthamoeba keratitis and Granulomatous amoebic encephalitis. Strathclyde Minor Groove Binders (S-MGBs) are a promising new class of anti-infective agent that have been shown to be effective against many infectious organisms.

Objectives: To synthesise and evaluate the anti-Acanthamoeba activity of a panel of S-MGBs, and therefore determine the potential of this class for further development.

Methods: A panel of 12 S-MGBs was synthesised and Anti-Acanthamoeba activity was determined using an alamarBlue™-based trophocidal assay against Acanthamoeba castellanii. Cross-screening against Trypanosoma brucei brucei, Staphylococcus aureus and Escherichia coli was used to investigate selective potency. Cytotoxicity against HEK293 cells allowed for selective toxicity to be measured. DNA binding studies were carried out using native mass spectrometry and DNA thermal shift assays.

Results: S-MGB-241 has an IC­50 of 6.6 µM against A. castellanii, comparable to the clinically used miltefosine (5.6 µM), and negligible activity against the other organisms. It was also found to have an IC50 >100 µM against HEK293 cells, demonstrating low cytotoxicity. S-MGB-241 binds to DNA as a dimer, albeit weakly compared to other S-MGBs previously studied. This was confirmed by DNA thermal shift assay with a ΔTm = 1 ± 0.1 oC.

Conclusions: Together, these data provide confidence that S-MGBs can be further optimised to generate new, potent treatments for Acanthameoba spp. infections. In particular, S-MGB-241, has been identified as a ‘hit’ compound that is selectively active against A. castellanii, providing a starting point from which to begin optimisation of DNA binding and potency.

Original languageEnglish
Article numberdkae221
Number of pages8
JournalJournal of Antimicrobial Chemotherapy
Early online date9 Jul 2024
DOIs
Publication statusE-pub ahead of print - 9 Jul 2024

Keywords

  • Acanthamoeba
  • Strathclyde Minor Groove Binders
  • anti-infective agents

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