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The lipid kinase phosphatidylinositol-4-OH kinase (PI(4)K) is identified as a target of the imidazopyrazines, a new antimalarial compound class that can inhibit several Plasmodium species at each stage of the parasite life cycle; the imidazopyrazines exert their inhibitory action by interacting with the ATP-binding pocket of PI(4)K.

It is unclear whether new antimalarial compounds may rapidly lose effectiveness in the field because of parasite resistance. Here, Corey et al.investigate the acquisition of drug resistance and the extent to which common resistance mechanisms decrease susceptibility to a diverse set of 50 antimalarial compounds.

Pepstatin is a known inhibitor of malarial proteases, but its activity varies between sources. Here, Istvanet al. identify a pepstatin ester as the active component of pepstatin preparations and show that this prodrug is activated by a Plasmodiumesterase, mutation of which can confer resistance to pepstatin and other compounds.

In a recent clinical trial for oral administration of cipargamin in individuals with malaria, there was an emergence of recrudescent parasites with a G358S mutation in PfATP4. In this work, the authors investigate the effect of this mutation on the function of the ATPase, on parasite growth and susceptibility to antimalarial drugs.

Present understanding of Plasmodium vivax biology is hampered by its inability to grow in vitro. Here, the authors developed an in vitro culture of its simian counterpart, P. cynomolgi, which shares morphological and phenotypic similarities with P. vivax, initiating a new phase in vivax research.

YAP is a transcriptional co-activator downstream of Hippo pathway that displays oncogenic but also tumour suppressive functions. Here, the authors perform an unbiased genome wide CRISPR screen and identify Trichorhinophalangeal syndrome 1 (TRPS1) that represses YAP/TEAD activity independently of Hippo pathway in breast cancer.

New antimalarials are urgently needed. Here, the authors identify Open Source Malaria compound, OSMS-106, as a reaction hijacking inhibitor of the malaria parasite protein synthesis machinery, with potential use for treatment and prophylaxis.

Integrated analyses of multiple large-scale screenings can be complicated by batch effects and technical artefacts. McFarland et al. introduce DEMETER2, a hierarchical model coupled with model-based normalization, which allows the assessment of differential dependencies across genes and cell lines.

The relationship between metabolomic and behavioral changes is not well understood. Here, the authors analyze metabolome changes in D. melanogaster heads and bodies during hunger and satiety, and develop the Flyscape tool to visualize the resulting metabolic networks and integrate them with other omics data.

Here, Reader et al. screen the Medicines for Malaria Venture Pandemic Response Box in parallel against Plasmodiumasexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. They identify two potent transmission-blocking drugs: a histone demethylase inhibitor ML324 and the antitubercular SQ109.

A new class of drugs, hexahydroquinolines, inhibits host haemoglobin endocytosis by Plasmodium falciparum and displays both therapeutic and transmission-blocking activities.

The bicyclic azetidines, a class of potent, well-tolerated antimalarial compounds that is active against multiple stages of the Plasmodium life-cycle, has been discovered following screens against libraries of compounds reminiscent of natural products.

The description of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of Plasmodium falciparum and good pharmacokinetic and safety properties, with potential for single-dose treatment, chemoprotection and prevention of transmission.

Sexual forms of malaria parasites are responsible for transmission to the mosquito. Anti-malarial drug resistance remains a serious problem and requires advent of new drug therapies. Here, the authors present a high-throughput screen of potential antimalarial compounds, identifying seventeen drug-like molecules specifically targeting transmission.

Mutations in two previously unreported Plasmodium falciparum genes, acetyl-CoA transporter (pfact) and UDP-galactose transporter (pfugt), convey resistance to two imidazolopiperazine antimalarial compounds.

The Tuberculosis Drug Accelerator, an experiment designed to facilitate collaboration in tuberculosis drug discovery by breaking down barriers among competing labs and institutions, has reached a 10-year landmark. We review the consortium’s achievements, advantages and limitations and advocate for the application of similar models to other diseases.

Here, de Vries et al. perform a pre-clinical characterization of the antimalarial compound MMV693183: the compound targets acetyl-CoA synthetase, has efficacy in humanized mice against Plasmodium falciparum infection, blocks transmission to mosquito vectors, is safe in rats, and pharmacokinetic-pharmacodynamic modeling informs about a potential oral human dosing regimen.

Genetic and environmental factors impact on lung function, important in the diagnosis of pulmonary diseases. Here the authors use imputation of genotypes to the 1000 Genomes Project reference panel to identify novel, low frequency variants associated with lung function.

Tres Cantos Open Lab is a collaborative initiative that integrates teams from academia and GlaxoSmithKline to enable rapid testing of innovative therapeutic hypotheses for endemic infectious diseases. Here, we provide an overview of the key scientific achievements in its first decade.

This study presents the first large scale transcriptional analysis of malaria parasites isolated from human patients, and defines three distinct transcriptional patterns that can be described as active growth, response to starvation and environmental stress response.

Treatment of female Anopheles gambiae mosquitoes with atovaquone causes arrest of the Plasmodium falciparum parasite in the midgut, and this holds promise for malaria eradication in areas with insecticide-resistant mosquito populations.

Ottilie et al. employ an experimental evolution approach to investigate the role of transcription factors in yeast chemical resistance. Most emergent mutations in resistant strains were enriched in transcription factor coding genes, highlighting their importance in drug resistance.

Tina Skinner-Adams et al. show that proguanil and the cyclization-blocked analogue, tBuPG, have potent, anti-plasmodial activity in vitro. This study suggests that a cyclization-blocked proguanil may be a superior combination partner for bc1-inhibitors to suppress the survival of malarial parasites.

Decoquinate is a drug used in veterinary practice, which displays antimalarial activity in vitro but has poor bioavailability. Here, the authors convert decoquinate into more soluble amide and carbamate derivatives and assess their efficacy against tuberculosis bacteria and apicomplexan parasites.

A large-scale study in Europe elucidating the contribution of pathogen clade and host species in disease hotspots caused by Ophidiomyces ophidiicola, the pathogen responsible for snake fungal disease.

This protocol describes the preparation of high-quality single-cell suspensions from the human placenta for downstream characterization, using droplet-based single-cell RNA sequencing platforms.

In this Review, Neafsey, Taylor and MacInnis discuss how population genomics approaches are currently used to study malaria parasites and mosquito vectors. They explore information that can be derived from such genomics approaches and discuss the use of relatedness-based measures of population variation to understand parasite and vector dynamics at highly resolved spatiotemporal scales.