Abstract
Naegleria fowleri is a pathogenic, thermophilic, free-living amoeba which causes primary amebic meningoencephalitis (PAM). Penetrating the olfactory mucosa, the brain-eating amoeba travels along the olfactory nerves, burrowing through the cribriform plate to its destination: the brain’s frontal lobes. The amoeba thrives in warm, freshwater environments, with peak infection rates in the summer months and has a mortality rate of approximately 97%. A major contributor to the pathogen’s high mortality is the lack of sensitivity of N. fowleri to current drug therapies, even in the face of combination-drug therapy. To enable rational drug discovery and design efforts we have pursued protein production and crystallography-based structure determination efforts for likely drug targets from N. fowleri. The genes were selected if they had homology to drug targets listed in Drug Bank or were nominated by primary investigators engaged in N. fowleri research. In 2017, 178 N. fowleri protein targets were queued to the Seattle Structural Genomics Center of Infectious Disease (SSGCID) pipeline, and to date 89 soluble recombinant proteins and 19 unique target structures have been produced. Many of the new protein structures are potential drug targets and contain structural differences compared to their human homologs, which could allow for the development of pathogen-specific inhibitors. Five of the structures were analyzed in more detail, and four of five show promise that selective inhibitors of the active site could be found. The 19 solved crystal structures build a foundation for future work in combating this devastating disease by encouraging further investigation to stimulate drug discovery for this neglected pathogen.
Highlights
In Australia in 1965, Fowler and Carter reported the first case of Naegleria fowleri infection, commonly referred to as the “brain-eating amoeba”, which is the only known species of the Naegleria genus associated with human disease [1]
Given the lack of efficacy of current drugs against N. fowleri and the urgent need for new drugs, we investigated the proteome of N. fowleri for likely drug targets attempting to enable further drug discovery efforts by producing material for characterization of the proteins
Additional targets were requested by the amoeba research community, leading to a total of 178 N. fowleri targets entering the Seattle Structural Genomics for Infectious Disease (SSGCID) structure determination pipeline
Summary
In Australia in 1965, Fowler and Carter reported the first case of Naegleria fowleri infection, commonly referred to as the “brain-eating amoeba”, which is the only known species of the Naegleria genus associated with human disease [1]. Infection rates of the amoeba increase during summer months causing the disease, primary amebic meningoencephalitis (PAM) [2, 3]. The National Institute of Allergy and Infectious Diseases (NIAID) has classified N. fowleri as a category B priority pathogen, the second highest class of priority organisms/biological agents. Category B pathogens typically have high mortality rates, are disseminated, may cause public panic and social disruption, and require special action for public health preparedness [2, 5]
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