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

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McGee, Leah M.C. and Carpinteyro Sanchez, Alemao G. and Perieteanu, Marina and Eskandari, Kaveh and Bian, Yan and Mackie, Logan and Young, Louise and Beveridge, Rebecca and Suckling, Colin J. and Roberts, Craig W. and Scott, Fraser J. (2024) Strathclyde Minor Groove Binders (S-MGBs) with activity against Acanthamoeba castellanii. Journal of Antimicrobial Chemotherapy, 79 (9). pp. 2251-2258. ISSN 0305-7453 (https://doi.org/10.1093/jac/dkae221)

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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 synthesize 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 synthesized 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 and discussion: S-MGB-241 has an IC 50 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 IC 50 > 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 ΔT m = 1 ± 0.1°C. Conclusions: Together, these data provide confidence that S-MGBs can be further optimized 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 optimization of DNA binding and potency.

ORCID iDs

McGee, Leah M.C. ORCID logoORCID: https://orcid.org/0000-0002-9896-0450, Carpinteyro Sanchez, Alemao G., Perieteanu, Marina, Eskandari, Kaveh, Bian, Yan, Mackie, Logan, Young, Louise, Beveridge, Rebecca ORCID logoORCID: https://orcid.org/0000-0003-0320-6496, Suckling, Colin J., Roberts, Craig W. ORCID logoORCID: https://orcid.org/0000-0002-0653-835X and Scott, Fraser J. ORCID logoORCID: https://orcid.org/0000-0003-0229-3698;
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