Small, free-living amoebae (FLA) are ubiquitous in nature and are found in soil, fresh water, and marine environments. Most of the FLA feed on bacteria and are of no medical importance, yet several genera and species of FLA are known to causes serious, usually fatal disease in humans and animals. Naegleria fowleri and Acanthamoeba spp. are the best known examples of pathogenic FLA. N. fowleri thrives in warm, freshwater and is the causative agent of primary amoebic meningoencephalitis (PAM). This disease is characterized by a fulminant, rapidly fatal encephalitic disease that most often afflicts healthy young humans. Acanthamoeba spp. are more ubiquitous and found in water (fresh and saline) and soil. Multiple species of Acanthamoeba are known to cause granulomatous amoebic encepahalitis (GAE), a chronic disease seen most often in immunocompromised hosts and those at risk of opportunistic infections. Acanthamoeba spp. also causes amoebic keratitis, skin, nasopharyngeal, and disseminated infections. The major problem for infections with any of the pathogenic FLA is the lack of effective therapeutics. PAM and GAE are usually fatal diseases, even if the infection is diagnosed promptly and treated with the best available drug regimens. Despite the severity of infections caused by FLA, there are few data available on new drugs and no concerted modern drug discovery or development efforts. The majority of the research literature on drug discovery for FLA consists of limited in vitro or in vivo studies with drugs already approved for other uses. The major goals of this project are to discover lead compounds for development as drugs to treat the central nervous system infections with pathogenic FLA. We will achieve these goals by screening a large library (<1100) bioactive drugs to identify novel chemotypes for the treatment of FLA. In addition, we will develop new in vitro drug susceptibility assays amenable for high throughput screening to support these research goals. Finally, we will adapt a novel microfluidics device that mimics the blood brain barrier to study the infection dynamics of pathogenic FLA and to assess the rate of killing of new compounds discovered in this proposal.
Small, free living amoebae of the genera Naegleria and Acanthamoeba cause fatal diseases in humans and animals, and new drugs are urgently required to treat the most deadly forms in the central nervous system as current therapies usually do not prevent death. Our goals are to discover a new series of compounds that can serve to accelerate the development of new drugs for these neglected emerging infections. Drug discovery for pathogenic FLA is particularly important for the southern tier states in the US, and although these infections are almost uniformly fatal, few studies have been conducted to identify better drugs to treat these infections. The goals of this study are to identify new drugs and develop a new blood brain barrier model for the assessment of central nervous system infections caused by protozoa.
|Thomas, Santana A L; von Salm, Jacqueline L; Clark, Shane et al. (2018) Keikipukalides, Furanocembrane Diterpenes from the Antarctic Deep Sea Octocoral Plumarella delicatissima. J Nat Prod 81:117-123|
|Rice, Christopher A; Colon, Beatrice L; Alp, Mehmet et al. (2015) Bis-benzimidazole hits against Naegleria fowleri discovered with new high-throughput screens. Antimicrob Agents Chemother 59:2037-44|