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 . 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. 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 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 . Pitavastatin demonstrated an EC of 0.5 to 1.9 ┬ÁM, 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 keratitis.

References

PubMed