# Sterol Biosynthesis Inhibitors as Drug Leads for the Treatment of Acanthamoeba Eye Infection

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $237,000

## Abstract

PROJECT SUMMARY/ABSTRACT
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 repurposing of the FDA-approved sterol biosynthesis inhibitors pitavastatin
and isavuconazonium for the treatment of AK. Identification of HMG-CoA reductase (HMGR) inhibitors and
sterol 14-demethylase (CYP51) inhibitors, which are amebicidal, and combination of novel cysticidal assay with
phenotypic trophozoite screen laid the foundation for this proposal. We have generated significant data
showing that (1) pitavastatin and isavuconazonium are potent trophocidals against three clinical strains of A.
castellanii, (2) isavuconazonium sulfate and its major metabolite isavuconazole exhibit low nanomolar potency
against trophozoites, (3) both isavuconazonium and isavuconazole suppress excystment of cysts into
trophozoites, (4) combination of pitavastatin and isavuconazole is synergistic on trophozoites, and (5)
isavuconazole targets A. castellanii CYP51 and parasite HMGR may be a relevant target for pitavastatin.
Based on these results, we propose to 1) evaluate mammalian cytotoxicity and trophocidal and cysticidal
activities of combination of pitavastatin and FDA-approved form isavuconazonium and compare that with the
effect of pitavastatin and isavuconazonium alone, 2) conduct tolerability and pharmacokinetic-
pharmacodynamic studies of topically administered pitavastatin and isavuconazonium, both monotherapy and
in combination therapy and 3) test in vivo efficacy of topical pitavastatin and isavuconazonium, alone and in
combination with each other, in an animal model of AK caused by Acanthamoeba of two different genotypes.
This study is a necessary step toward repurposing of topically administered pitavastatin and isavuconazonium
for the treatment of AK. To successfully achieve the proposal goals, we rely on our existing collaboration that
combines the unique expertise of Dr. Debnath (PI) in Acanthamoeba parasite biology and Dr. Afshari in
ophthalmology. Drs. Debnath and Afshari's expertise and experience in parasitic eye infection has potential to
elevate our drug repurposing platform to a translational level.

## Key facts

- **NIH application ID:** 10870343
- **Project number:** 1R21EY036216-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Anjan Debnath
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $237,000
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10870343

## Citation

> US National Institutes of Health, RePORTER application 10870343, Sterol Biosynthesis Inhibitors as Drug Leads for the Treatment of Acanthamoeba Eye Infection (1R21EY036216-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10870343. Licensed CC0.

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