The anticancer human mTOR inhibitor sapanisertib potently inhibits multiple Plasmodium kinases and life cycle stages.

Compounds acting on multiple targets are critical to combating antimalarial drug resistance. Here, we report that the human "mammalian target of rapamycin" (mTOR) inhibitor sapanisertib has potent prophylactic liver stage activity, in vitro and in vivo asexual blood stage (ABS) activity, and transmission-blocking activity against the protozoan parasite Plasmodium spp. Chemoproteomics studies revealed multiple potential Plasmodium kinase targets, and potent inhibition of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4Kß) and cyclic guanosine monophosphate-dependent protein kinase (PKG) was confirmed in vitro. Conditional knockdown of PI4Kß in ABS cultures modulated parasite sensitivity to sapanisertib, and laboratory-generated P. falciparum sapanisertib resistance was mediated by mutations in PI4Kß. Parasite metabolomic perturbation profiles associated with sapanisertib and other known PI4Kß and/or PKG inhibitors revealed similarities and differences between chemotypes, potentially caused by sapanisertib targeting multiple parasite kinases. The multistage activity of sapanisertib and its in vivo antimalarial efficacy, coupled with potent inhibition of at least two promising drug targets, provides an opportunity to reposition this pyrazolopyrimidine for malaria.

Co-infection by dimorphic fungi in tuberculosis patients in Kenya.

Background: Dimorphic fungi may cause infections and symptoms similar to tuberculosis (TB), in humans and animals. Such infections, individually or concurrently with TB, have been identified in cattle in Kenya, raising the possibility of infections in other animals, including humans. The study aimed to identify and quantify dimorphic fungi co-infection in persons with TB. Methods: Smear-positive sputum samples, 400, were obtained from TB clinics between October 2016 and November 2017. The samples were examined microscopically for yeast fungi, cultured for isolation of yeast, conversion to molds, and conversion from molds to yeasts. The isolates were characterized morphologically. Results: Blastopores, with morphological characteristics of Paracoccidiodes and Blastomyces, were observed in 37 smears of the sputum samples. Similar yeast cells were observed in smears of the sputum cultures. The yeast cultures were converted to molds on incubation at room temperature and back to yeasts on incubation at 37°C. Conclusion: Dimorphic fungi, morphologically identified as Paracoccidiodes and Blastomyces, concomitantly infect a proportion of TB patients in the study area. It is recommended that routine diagnosis for TB should consider infection or co-infection by dimorphic fungi for institution of appropriate treatment.

Chemotherapy for human schistosomiasis: how far have we come? What's new? Where do we go from here?

Globally, schistosomiasis threatens more than 700 million lives, mostly children, in poor localities of tropical and sub-tropical areas with morbidity due to acute and chronic pathological manifestations of the disease. After a century since the first antimonial-based drugs were introduced to treat the disease, anti-schistosomiasis drug development is again at a bottleneck with only one drug, praziquantel, available for treatment purposes. This review focuses on promising chemotypes as potential starting points in a drug discovery effort to meet the urgent need for new schistosomicides.