A major cause of the paucity of new starting points for drug discovery is the lack of interaction between academia and industry. Much of the global resource in biology is present in universities, whereas the focus of medicinal chemistry is still largely within industry. Open source drug discovery, with sharing of information, is clearly a first step towards overcoming this gap. But the interface could especially be bridged through a scale-up of open sharing of physical compounds, which would accelerate the finding of new starting points for drug discovery. The Medicines for Malaria Venture Malaria Box is a collection of over 400 compounds representing families of structures identified in phenotypic screens of pharmaceutical and academic libraries against the Plasmodium falciparum malaria parasite. The set has now been distributed to almost 200 research groups globally in the last two years, with the only stipulation that information from the screens is deposited in the public domain. This paper reports for the first time on 236 screens that have been carried out against the Malaria Box and compares these results with 55 assays that were previously published, in a format that allows a meta-analysis of the combined dataset. The combined biochemical and cellular assays presented here suggest mechanisms of action for 135 (34%) of the compounds active in killing multiple life-cycle stages of the malaria parasite, including asexual blood, liver, gametocyte, gametes and insect ookinete stages. In addition, many compounds demonstrated activity against other pathogens, showing hits in assays with 16 protozoa, 7 helminths, 9 bacterial and mycobacterial species, the dengue fever mosquito vector, and the NCI60 human cancer cell line panel of 60 human tumor cell lines. Toxicological, pharmacokinetic and metabolic properties were collected on all the compounds, assisting in the selection of the most promising candidates for murine proof-of-concept experiments and medicinal chemistry programs. The data for all of these assays are presented and analyzed to show how outstanding leads for many indications can be selected. These results reveal the immense potential for translating the dispersed expertise in biological assays involving human pathogens into drug discovery starting points, by providing open access to new families of molecules, and emphasize how a small additional investment made to help acquire and distribute compounds, and sharing the data, can catalyze drug discovery for dozens of different indications. Another lesson is that when multiple screens from different groups are run on the same library, results can be integrated quickly to select the most valuable starting points for subsequent medicinal chemistry efforts.

Antimalarial drugs have thus far been chiefly derived from two sources—natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.

Graphical AbstractHighlights d Human malaria parasites interact non-competitively with their mosquito vectors d Mosquito hormone signaling co-regulates egg and parasite development d Parasites use host lipids for their growth via a mosquito lipid transporter d Parasites respond to mosquito metabolism with consequences for vector controlThe development of the malaria-causing parasite Plasmodium falciparum depends on its ability to exploit the sexual cycle of its mosquito host in a noncompetitive manner. SUMMARYTransmission of malaria parasites occurs when a female Anopheles mosquito feeds on an infected host to acquire nutrients for egg development. How parasites are affected by oogenetic processes, principally orchestrated by the steroid hormone 20hydroxyecdysone (20E), remains largely unknown.Here we show that Plasmodium falciparum development is intimately but not competitively linked to processes shaping Anopheles gambiae reproduction. We unveil a 20E-mediated positive correlation between egg and oocyst numbers; impairing oogenesis by multiple 20E manipulations decreases parasite intensities. These manipulations, however, accelerate Plasmodium growth rates, allowing sporozoites to become infectious sooner. Parasites exploit mosquito lipids for faster growth, but they do so without further affecting egg development. These results suggest that P. falciparum has adopted a non-competitive evolutionary strategy of resource exploitation to optimize transmission while minimizing fitness costs to its mosquito vector. Our findings have profound implications for currently proposed control strategies aimed at suppressing mosquito populations.

Every year the bites of Anopheles mosquitoes kill hundreds of thousands of people, mostly young African children, by transmitting deadly Plasmodium falciparum malaria parasites. Since the turn of the century, efforts to prevent transmission of these parasites via the mass distribution of insecticide-treated bed nets have been extremely successful, causing an unprecedented reduction in malaria deaths 1 . However, resistance to insecticides has become widespread in Anopheles populations [2][3][4] , threatening a global resurgence of the disease and making the generation of effective new malaria control tools an urgent public health priority. Here, we show that development of P. falciparum can be rapidly and completely blocked when Anopheles gambiae females uptake low concentrations of specific antimalarials from treated surfaces, simulating contact with a bed net. Mosquito exposure to atovaquone prior to or shortly after P. falciparum infection causes full parasite arrest in the female midgut, preventing transmission of infection. Similar transmission-blocking effects are achieved with other cytochrome B inhibitors, demonstrating that parasite mitochondrial function is a good target for parasite killing. Incorporating these effects into a model of malaria transmission dynamics predicts that the inclusion of Plasmodium inhibitors on mosquito nets would significantly mitigate the global health impact of insecticide resistance. This study identifies a powerful new strategy for blocking Plasmodium transmission by Anopheles females, with promising implications for malaria eradication efforts.Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: