Discovery of repurposing drug candidates for the treatment of diseases caused by pathogenic free-living amoebae

Abstract

Diseases caused by pathogenic free-living amoebae include primary amoebic meningoencephalitis (Naegleria fowleri), granulomatous amoebic encephalitis (Acanthamoeba spp.), Acanthamoeba keratitis, and Balamuthia amoebic encephalitis (Balamuthia mandrillaris). Each of these are difficult to treat and have high morbidity and mortality rates due to lack of effective therapeutics. In pursuit of repurposing drugs for chemotherapies, we conducted a high throughput phenotypic screen of 12,000 compounds from the Calibr ReFRAME library. We discovered a total of 58 potent inhibitors (IC50 90% for the diseases caused by Balamuthia mandrillaris, Naegleria fowleri, and Acanthamoeba spp. With hundreds of cases in the United States and many more cases reported worldwide, there is still an urgent clinical need for effective diagnosis and specific treatments discovered against these opportunistic parasites. Drug repurposing is a powerful approach for drug-discovery because it significantly improves the discovery time, reduces the amount of resources, and decreases costs required to advance lead candidate drugs of interest into the clinic. This is extremely helpful for neglected diseases including pathogenic FLA where there is a need for new active therapies with limited budgets. This report addresses the discovery of new active drugs with potential for repurposing, multiple new drug classes that inhibit pathogenic FLA, and numerous putative drug targets that can be used as tools for further investigation and structure-based drug design.