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Aquaglyceroporins (AQPs) are membrane proteins that function in osmoregulation and the uptake of low molecular weight solutes, in particular glycerol and urea. The AQP family is highly conserved, with two major subfamilies having arisen very early in prokaryote evolution and retained by eukaryotes. A complex evolutionary history indicates multiple lineage-specific expansions, losses and not uncommonly a complete loss. Consequently, the AQP family is highly evolvable and has been associated with significant events in life on Earth. In the African trypanosomes, a role for the AQP2 paralogue, in sensitivity to two chemotherapeutic agents, pentamidine and melarsoprol, is well established, albeit with the mechanisms for cell entry and resistance unclear until very recently. Here, we discuss AQP evolution, structure and mechanisms by which AQPs impact drug sensitivity, suggesting that AQP2 stability is highly sensitive to mutation while serving as the major uptake pathway for pentamidine. [ABSTRACT FROM AUTHOR]

Clemson University researchers have made advancements in the treatment of sleeping sickness caused by the African trypanosome, Trypanosoma brucei. The researchers tested phosphonate inhibitors, originally developed for the treatment of glioblastoma multiforme, against T. brucei and found them to be potent enzyme inhibitors and trypanocides. One particular inhibitor, HEX, showed promise as a lead compound for further development. These findings provide potential new therapeutic options for sleeping sickness treatment. [Extracted from the article]

SUMMARY: Trypanosomes (genus Trypanosoma) are parasites of humans, and wild and domestic mammals, in which they cause several economically and socially important diseases, including sleeping sickness in Africa and Chagas disease in the Americas. Despite the development of numerous molecular diagnostics and increasing awareness of the importance of these neglected parasites, there is currently no universal genetic barcoding marker available for trypanosomes. In this review we provide an overview of the methods used for trypanosome detection and identification, discuss the potential application of different barcoding techniques and examine the requirements of the ‘ideal’ trypanosome genetic barcode. In addition, we explore potential alternative genetic markers for barcoding Trypanosoma species, including an analysis of phylogenetically informative nucleotide changes along the length of the 18S rRNA gene. [ABSTRACT FROM AUTHOR]

New drugs against Trypanosoma brucei, the causative agent of Human African Trypanosomiasis, are urgently needed to replace the highly toxic and largely ineffective therapies currently used. The trypanosome alternative oxidase (TAO) is an essential and unique mitochondrial protein in these parasites and is absent from mammalian mitochondria, making it an attractive drug target. The structure and function of the protein are now well characterized, with several inhibitors reported in the literature, which show potential as clinical drug candidates. In this review, we provide an update on the functional activity and structural aspects of TAO. We then discuss TAO inhibitors reported to date, problems encountered with in vivo testing of these compounds, and discuss the future of TAO as a therapeutic target. [ABSTRACT FROM AUTHOR]

The oral sleeping sickness candidate could boost a global push to interrupt transmission of the parasitic disease by 2030. [ABSTRACT FROM AUTHOR]

Considering the epidemic situation of gambiense human African trypanosomiasis (HAT) at the end of the twentieth century, the World Health Organization (WHO) and partners strengthened disease control and surveillance. Over the last 15 years, the activities implemented through the National Control Programmes have brought gambiense HAT under control and now its elimination is deemed as an achievable goal. In 2012, WHO targeted gambiense HAT for elimination as a public health problem by 2020. The final goal will be the sustainable disease elimination by 2030, defined as the interruption of the transmission of gambiense HAT. The elimination is considered feasible, because of the epidemiological vulnerability of the disease, the current state of control, the availability of strategies and tools and international commitment and political will. Integration of activities in the health system is needed to ensure the sustainability of the elimination. The development of user-friendly diagnostic and treatment tools will facilitate the integration process. Adequate funding is needed to implement activities, but also to support research that will make the elimination sustainable. A long-term commitment by donors is needed and ownership of the process by endemic countries is critical. [ABSTRACT FROM AUTHOR]

Six dietary isothiocyanates, allyl-isothiocyanate, benzyl-isothiocyanate, phenylethyl-isothiocyanate, sulforaphane, erucin, and iberin, were tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. All isothiocyanates showed a dose-dependent effect on the growth of trypanosomes. Five compounds displayed MIC values of 10 μM and GI50 values of around 1.5 μM, while allyl-isothiocyanate exhibited values of 100 and 11 μM, respectively. The compounds showed similar cytotoxic activities against human HL-60 cells with GI50 values of 1-4 μM and MIC values of 10-100 μM. Short-term experiments revealed that, with the exception of allyl- isothiocyanate, isothiocyanates at a concentration of 10 μM kill trypanosomes within 1-4 h of incubation. In contrast, HL-60 cellswere not affected by any of the compounds in short-termincubation experiments. Sulforaphane, the most intensively studied isothiocyanate, was also investigated for its in vivo trypanocidal activity. However, administration of 50mg/kg sulforaphane orally or intraperitoneally for four days had no effect on the parasitaemia in mice infected with T. brucei compared to control animals treated with vehicle alone. [ABSTRACT FROM AUTHOR]

Four β-lactone-γ-lactam proteasome inhibitors of natural origin were tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. All four compounds displayed activities in the nanomolar range. The most trypanocidal compounds with 50% growth inhibition (GI50) values of around 3 nM were the bromine and iodine analogues of salinosporamide A, a potent proteasome inhibitor produced by the marine actinomycete Salinispora tropica. In general, trypanosomes were more susceptible to the compounds than were human HL-60 cells. The data support the potential of β-lactone-γ-lactam proteasome inhibitors for rational anti-trypanosomal drug development. [ABSTRACT FROM AUTHOR]

Trypanosoma brucei gambiense sleeping sickness follows a long asymptomatic phase and persists in ancient foci from which epidemic clinical disease arises. A putative focus of T. b. gambiense infections has been identified, initially in mothers and young children, on the Lake Albert shoreline of Western Uganda leading to mass screening of 6207 individuals in September 2008. T. b. gambiense infections were identified by Card Agglutination Test for Trypanosomiasis (CATT) and sub-species-specific PCR although parasitological methods failed to confirm any patent trypanosome infections. In April 2009, CATT positives were re-visited; diagnosis of individuals by CATT and PCR was unstable over the two time points and parasites remained undetected, even using mini Anion Exchange Centrifugation Technique (mAECT). These observations suggest the possibility of a silent focus of disease, where all infected individuals are in a latent stage, and highlight our limited understanding of the local natural history and disease progression of T. b. gambiense in children and adults. [ABSTRACT FROM PUBLISHER]

Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) which is fatal if left untreated. This disease occurs in 36 African countries, south of the Sahara, where 60 million people are at risk of acquiring infection. The current chemotherapy relies on only four drugs, three of which were developed more than 60 years ago. These drugs have many limitations, ranging from oral inabsorption, acute toxicities, short duration of action and the emergence of trypanosomal resistance. Despite decades of use of most of the current trypanocides, little is known about their mode of action. That being said, African trypanosomes continue to be among the most extensively studied parasitic protists to date. Many of their intriguing biological features have been well documented and can be viewed as attractive targets for antitrypanosomal chemotherapy. A considerable number of natural products with diverse molecular structures have revealed antiparasitic potency in the laboratory and represent interesting lead compounds for the development of new and urgently needed antiparasitics. The major validated drug targets in T. brucei are discussed with particular emphasis on those known to be attacked by natural compounds. [ABSTRACT FROM AUTHOR]

Following a period characterized by severe epidemics of sleeping sickness, restoration of effective control and surveillance systems has raised the question of eliminating the disease from sub-Saharan Africa. Given sufficient political and financial support, elimination is now considered a reasonable aim in countries reporting zero or less than 100 cases per year. This success may lead health authorities across the affected region to downgrade the disease from 'neglected' to simply being ignored. In view of the significant levels of under-reporting of sleeping sickness mortality in rural communities, this could be a short-sighted policy. Loss of capacity to deal with new epidemics, which can arise as a consequence of loss of commitment or civil upheaval, would have serious consequences. The present period should be seen as a clear opportunity for public-private partnerships to develop simpler and more cost-effective tools and strategies for sustainable sleeping sickness control and surveillance, including diagnostics, treatment and vector control. [ABSTRACT FROM AUTHOR]

Human sleeping sickness in Africa, caused by Trypanosoma brucei spp. raises a number of questions. Despite the widespread distribution of the tsetse vectors and animal trypanosomiasis, human disease is only found in discrete foci which periodically give rise to epidemics followed by periods of endemicity A key to unravelling this puzzle is a detailed knowledge of the aetiological agents responsible for different patterns of disease - knowledge that is difficult to achieve using traditional microscopy. The science of molecular epidemiology has developed a range of tools which have enabled us to accurately identify taxonomic groups at all levels (species, subspecies, populations, strains and isolates). Using these tools, we can now investigate the genetic interactions within and between populations of Trypanosoma brucei and gain an understanding of the distinction between human- and nonhuman-infective subspecies. In this review, we discuss the development of these tools, their advantages and disadvantages and describe how they have been used to understand parasite genetic diversity, the origin of epidemics, the role of reservoir hosts and the population structure. Using the specific case of T.b. rhodesiense in Uganda, we illustrate how molecular epidemiology has enabled us to construct a more detailed understanding of the origins, generation and dynamics of sleeping sickness epidemics. [ABSTRACT FROM AUTHOR]