Short-course combination treatment for experimental chronic Chagas disease.

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects millions of people in the Americas and across the world, leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects because of long treatment durations. Better treatment options are therefore urgently required. Here, we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers an opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites; however, combining these pyrrolopyrimidines with a subefficacious dose of BNZ can clear all parasites in vitro after 5 days. These findings were replicated in a clinically predictive in vivo model of chronic Chagas disease, where 5 days of treatment with the combination was sufficient to prevent parasite relapse. Comprehensive mechanism of action studies, supported by ligand-structure modeling, show that compounds from this pyrrolopyrimidine series inhibit the Qi active site of T. cruzi cytochrome b, part of the cytochrome bc1 complex of the electron transport chain. Knowledge of the molecular target enabled a cascade of assays to be assembled to evaluate selectivity over the human cytochrome b homolog. As a result, a highly selective and efficacious lead compound was identified. The combination of our lead compound with BNZ rapidly clears T. cruzi parasites, both in vitro and in vivo, and shows great potential to overcome key issues associated with currently available treatments.

DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1.

New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.

Delftia tsuruhatensis TC1 symbiont suppresses malaria transmission by anopheline mosquitoes.

Malaria control demands the development of a wide range of complementary strategies. We describe the properties of a naturally occurring, non-genetically modified symbiotic bacterium, Delftia tsuruhatensis TC1, which was isolated from mosquitoes incapable of sustaining the development of Plasmodium falciparum parasites. D. tsuruhatensis TC1 inhibits early stages of Plasmodium development and subsequent transmission by the Anopheles mosquito through secretion of a small-molecule inhibitor. We have identified this inhibitor to be the hydrophobic molecule harmane. We also found that, on mosquito contact, harmane penetrates the cuticle, inhibiting Plasmodium development. D. tsuruhatensis TC1 stably populates the mosquito gut, does not impose a fitness cost on the mosquito, and inhibits Plasmodium development for the mosquito's life. Contained field studies in Burkina Faso and modeling showed that D. tsuruhatensis TC1 has the potential to complement mosquito-targeted malaria transmission control.

Tropical Laboratory Initiative: An innovative model for laboratory medicine in rural areas.

BACKGROUND: Communities in rural, low-resource settings often lack access to reliable diagnostics. This leads to missed and misdiagnosed cases of disease and contributes to morbidity and mortality. OBJECTIVE: This paper describes a model for providing local laboratory services to rural areas of Ghana, and provides suggestions on how it could be adapted and expanded to serve populations in a range of rural communities. METHODS: The Tropical Laboratory Initiative (TLI) system in Ghana comprises one central laboratory where samples delivered from clinics by motorbike riders are analysed. Test requests and results are communicated on a mHealth application, and the patient does not have to visit the laboratory or travel beyond the clinic to receive a test. The TLI also serves as a research base. The laboratory is accredited by the National Health Insurance Authority, and accepts the national health insurance. The TLI serves several communities in Amansie West, Ashanti region, and currently works with 10 clinics. The nearest hospital is a one-hour drive away and is the only other nearby facility for diagnostics beyond basic rapid tests. RESULTS: Demand for services has increased yearly since the launch in 2010, and the TLI currently provides over 1000 tests to approximately 350 patients monthly. The majority of patients are female, and the most common tests are for antenatal care. Our experience demonstrates that laboratory services can be affordable and most components already exist, even in rural areas. CONCLUSION: Ministries of health in low-resource settings should consider this model to complement the rapid tests available in clinics. Integrating with an insurance system promotes financial sustainability.

A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N-[3-[(Benzimidazol-2-yl)amino]propyl]amides.

Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group.