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Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young and malnourished children from low- and middle-income countries, with no vaccine or effective treatment. Here we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor, designed to be active at the infection site in the gastrointestinal tract and undergo rapid metabolism in the liver. By using mutational analysis and crystal structure, we show that EDI048 binds to highly conserved amino acid residues in the ATP-binding site. EDI048 is orally efficacious in an immunocompromised mouse model despite negligible circulating concentrations, thus demonstrating that gastrointestinal exposure is necessary and sufficient for efficacy. In neonatal calves, a clinical model of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of diarrhoea and significant reduction in faecal oocyst shedding. Safety and pharmacological studies demonstrated predictable metabolism and low systemic exposure of EDI048, providing a substantial safety margin required for a paediatric indication. EDI048 is a promising clinical candidate for the treatment of life-threatening paediatric cryptosporidiosis., (© 2024. The Author(s).)

Outbreaks of suspected tick-borne disease (redwater fever) have been reported in captive deer of the Scottish Highlands. In this pilot study, polymerase chain reaction and amplicon sequencing were used to detect tick-borne pathogens in opportunistically collected blood and spleen samples from 63 (healthy, n = 44; diseased, n = 19) cervids, and 45 questing and feeding ticks ( Ixodes ricinus ) from the outbreak sites in 2021-2022. Potentially pathogenic Babesia species were detected in deer but not identified in ticks, Anaplasma phagocytophilum was detected in both deer and ticks, and Borrelia afzelii was detected in ticks but not in deer. Sequencing confirmed Babesia capreoli and Babesia cf. odocoilei parasitemia in clinically healthy red deer ( Cervus elaphus ), B. capreoli parasitemia in clinically healthy domestic reindeer ( Rangifer tarandus tarandus ), and two cases of B. cf. odocoilei -associated hemolytic anemia in white-lipped deer ( Cervus albirostris ), of which one was fatal despite imidocarb treatment. White-lipped deer appear to be highly susceptible to babesiosis caused by B. cf. odocoilei . This investigation highlights the importance of disease surveillance, including molecular diagnostics, for the detection of emerging tick-borne pathogens in managed populations of cervids.

Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.

Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient K p as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios ( K p,uu ) to cure a CNS disease such as HAT.

A series of 5-aryl-2-amino- i midazo t hia d iazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum ( Pf ) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 ( 1 ), which demonstrates potent cellular activity against Pf 3D7 (EC 50 = 0.006 μM) and achieves "artemisinin-like" kill kinetics in vitro with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf -humanized severe combined immunodeficient mouse model. INE963 ( 1 ) also exhibits a high barrier to resistance in drug selection studies and a long half-life ( T 1/2 ) across species. These properties suggest the significant potential for INE963 ( 1 ) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 ( 1 ) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.