In Vitro Effect of Pitavastatin and Its Synergistic Activity with Isavuconazole against Acanthamoeba castellanii.

Hye Jee Hahn,Jose Ignacio Escrig,Brian Shing,Anjan Debnath

doi:10.3390/pathogens9090681

Hye Jee Hahn, Jose Ignacio Escrig + Show 2 more

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https://doi.org/10.3390/pathogens9090681

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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. Current treatment for AK relies on a combination of chlorhexidine, propamidine isethionate, and polyhexamethylene biguanide. However, the current regimen includes an aggressive disinfectant and in 10% of cases recurrent infection ensues. Therefore, development of efficient and safe drugs is a critical unmet need to avert blindness. Acanthamoeba sterol biosynthesis includes two essential enzymes HMG-CoA reductase (HMGR) and sterol 14-demethylase (CYP51), and we earlier identified a CYP51 inhibitor isavuconazole that demonstrated nanomolar potency against A. castellanii trophozoites. In this study, we investigated the effect of well-tolerated HMGR inhibitors and identified pitavastatin that is active against trophozoites of three different clinical strains of A. castellanii. Pitavastatin demonstrated an EC50 of 0.5 to 1.9 µM, depending on strains. Combination of pitavastatin and isavuconazole is synergistic and led to 2- to 9-fold dose reduction for pitavastatin and 11- to 4000-fold dose reduction for isavuconazole to achieve 97% of growth inhibition. Pitavastatin, either alone or in combination with isavuconazole, may lead to repurposing for the treatment of Acanthamoeba keratitis.

Highlights

Painful blinding keratitis is caused by the free-living ameba Acanthamoeba and can occur in healthy individuals wearing contact lenses [1]
hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGR) inhibitors developed as cholesterol lowering drugs, known as statins, prevent the conversion of HMG-CoA to mevalonate, resulting in the inhibition of the isoprenoid biosynthesis and the downstream sterol biosynthesis [22]
Atorvastatin and rosuvastatin exhibited similar EC50, ranging from 10 to 12.5 μM, we demonstrated that the HMGR

Summary

Introduction

Painful blinding keratitis is caused by the free-living ameba Acanthamoeba and can occur in healthy individuals wearing contact lenses [1]. Acanthamoeba keratitis (AK) is a rare but serious infection of the eye that causes inflammation in the clear front surface of the eye (the cornea) and can result in permanent visual impairment or blindness. Acanthamoeba is common in nature and can be found in soil, air and water, including insufficiently chlorinated pools, hot tubs, tap and shower water. Cyst resistance to therapeutic agents, and recurrence of infection due to Acanthamoeba excystment, remain a challenge for disease prevention and cure. AK is most common in people who wear contact lenses, but anyone can develop the infection [2,3,4]

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