Latrunculin B as a new drug lead for the treatment of Acanthamoeba keratitis

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PROJECT SUMMARY Acanthamoeba keratitis (AK) can occur in healthy individuals wearing contact lenses and it is a painful blinding infection of the cornea caused by a free-living ameba Acanthamoeba. Complications include chronic ocular inflammation, corneal melting and scarring. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, in 10% of cases recurrent infection ensues, because of the difficulty in killing both trophozoites and double-walled cysts. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Because AK is a rare disease, there is a paucity of drug discovery efforts by the pharmaceutical industry and drug discovery for this infection largely relies on academic research centers. To reduce the cost, time and risk associated with the development of new AK therapies, we focused on the development of topical latrunculin B that completed Phase I/II safety, tolerability and efficacy study in patients with ocular hypertension and glaucoma for the treatment of AK. Marine natural product latrunculin B, which targets actin cytoskeleton of A. castellanii trophozoites and found amebicidal in a phenotypic screen, laid the foundation for this proposal. Data related to this proposal show that (1) latrunculin B is amebicidal against three clinical strains of A. castellanii, (2) a short treatment with low concentration of latrunculin B led to depolymerization of actin filaments and subsequent disorganization of acanthopodia in A. castellanii trophozoites, and (3) a novel image-based cysticidal assay developed by the PI could be used to investigate the cysticidal effect of latrunculin B. Based on these data, we propose to 1) test latrunculin B, against trophozoites and cysts of multiple genotypes of Acanthamoeba, 2) conduct tolerability and pharmacokinetic-pharmacodynamic studies of topically administered latrunculin B for AK, and 3) test in vivo efficacy of topical latrunculin B in an animal model of AK caused by Acanthamoeba of two different genotypes. This study is a necessary step toward obtaining orphan drug designation of topically administered latrunculin B for the treatment of AK. Given a deficit of the validated drug targets in Acanthamoeba, this study will also enhance the development of novel targeted treatment option for AK. The results obtained in this work may be expanded to other free-living amebae. To successfully achieve the proposal goals, we rely on our collaboration that combines the unique expertise of Dr. Debnath (PI) in Acanthamoeba parasite biology and Dr. Afshari in ophthalmology (Co-Investigator). Drs. Debnath and Afshari’s expertise and experience has potential to elevate our drug discovery platform to a translational level.