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- Title
Strathclyde minor groove binders (S-MGBs) with activity against Acanthamoeba castellanii.
- Authors
Mcgee, Leah M C; Sanchez, Alemao G Carpinteyro; Perieteanu, Marina; Eskandari, Kaveh; Bian, Yan; Mackie, Logan; Young, Louise; Beveridge, Rebecca; Suckling, Colin J; Roberts, Craig W; Scott, Fraser J
- 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 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 Δ T 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.
- Subjects
ACANTHAMOEBA castellanii; ACANTHAMOEBA keratitis; ANTI-infective agents; CYTOTOXINS; TRYPANOSOMA brucei
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2024, Vol 79, Issue 9, p2251
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dkae221