Discovery of anti-amoebic inhibitors from screening the MMV Pandemic Response Box on Balamuthia mandrillaris, Naegleria fowleri and Acanthamoeba castellanii

Abstract

Pathogenic free-living amoebae, Balamuthia mandrillaris, Naegleria fowleri and several Acanthamoeba species are the etiological agents of severe brain diseases, with case mortality rates >90%. A number of constraints including misdiagnosis and partially effective treatments lead to these high fatality rates. The unmet medical need is for rapidly acting, highly potent new drugs to reduce these alarming mortality rates. Herein, we report the discovery of new drugs as potential anti-amoebic agents. We used the CellTiter-Glo 2.0 high-throughput screening methods to screen the Medicines for Malaria Ventures (MMV) Pandemic Response Box in a search for new active chemical scaffolds. Initially we screened the library as a single-point assay at 10 and 1 µM. From these data, we reconfirmed hits by conducting quantitative dose response assays and identified 12 hits against B. mandrillaris, 29 against N. fowleri and 14 against A. castellanii ranging from nanomolar to low micromolar potency. We further describe 11 novel molecules with activity against B. mandrillaris, 22 against N. fowleri and 9 against A. castellanii. These structures serve as a starting point for medicinal chemistry studies and demonstrate the utility of phenotypic screening for drug discovery to treat diseases caused by free-living amoebae.

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

“…FDA-approved isavuconazole (marketed as a prodrug Cresemba TM ) has a good safety profile and is well-tolerated in humans [ 30 ]. Isavuconazole CC 50 against human A549 lung carcinoma cells was found > 10 µM [ 31 ]. This provides a selectivity index of about 400 to 10,000, depending on the strains of A. castellanii .…”

Balamuthia mandrillaris infection in China: a retrospective report of 28 cases

“…However, currently, there are no reports of cases treated with this drug. Other potential drugs have also been screened in vitro ; however, the clinical efficacy and side effects of these drugs need to be verified clinically [ 39 , 40 ].…”

The increasing importance of Vermamoebavermiformis

“…Moreover, other compounds such as Corifungin revealed potent anti‐ Naegleria effects (Debnath et al, 2012). Another recent study elucidated 22 novel compounds against free‐living amoebae (Rice et al, 2020). These nano‐conjugated compounds and novel compounds could be utilized to develop biosensors in combination with drug release in target tissues, in keratitis patients or combined with photodynamic therapy, which has shown promise against Acanthamoeba infections (Aqeel et al, 2015).…”