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Identification of Four Amoebicidal Nontoxic Compounds by a Molecular Docking Screen of Naegleria fowleri Sterol ?8-?7-Isomerase and Phenotypic Assays.


ABSTRACT: Naegleria fowleri is a free-living amoeba causing primary amoebic meningoencephalitis, a rapid-onset brain infection in humans with over 97% mortality rate. Despite some progress in the treatment of the disease, there is no single, proven, evidence-based treatment with a high probability of cure. Here we report the chemical library screening and experimental identification of four new compounds with amoebicidal effects against N. fowleri. The chemical library was screened by molecular docking against a homology model of sterol ?8-?7 isomerase (NfERG2). Thirty top-ranking hits were then tested in a cell-based assay for antiproliferative/amoebicidal activities. Eight chemicals exhibited nearly 100% inhibition of N. fowleri at 50 ?M, with the EC50 values ranging from 6 to 25 ?M. A cell toxicity assay using human HEK-293 cells was also performed. Four of the compounds preferentially kill amoeba cells with no apparent human cell toxicities. These compounds fall into two distinct chemical scaffolds with druglike properties.

SUBMITTER: Shi D 

PROVIDER: S-EPMC7085920 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Identification of Four Amoebicidal Nontoxic Compounds by a Molecular Docking Screen of <i>Naegleria fowleri</i> Sterol Δ8-Δ7-Isomerase and Phenotypic Assays.

Shi Da D   Chahal Kirti Kandhwal KK   Oto Patricia P   Nothias Louis-Felix LF   Debnath Anjan A   McKerrow James H JH   Podust Larissa M LM   Abagyan Ruben R  

ACS infectious diseases 20191017 12


<i>Naegleria fowleri</i> is a free-living amoeba causing primary amoebic meningoencephalitis, a rapid-onset brain infection in humans with over 97% mortality rate. Despite some progress in the treatment of the disease, there is no single, proven, evidence-based treatment with a high probability of cure. Here we report the chemical library screening and experimental identification of four new compounds with amoebicidal effects against <i>N. fowleri</i>. The chemical library was screened by molecu  ...[more]

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