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Malaria parasites are evolutionarily prepared to resist drug attack. Resistance is emerging to even the latest frontline combination therapies, which target the blood stages of the Plasmodium parasite. As an alternative strategy, Antonova-Koch et al. investigated the possibilities of drugs against liver-stage parasites (see the Perspective by Phillips and Goldberg). To do so, they devised a luciferase-reporter drug screen for the rodent parasite Plasmodium berghei. Three rounds of increasingly stringent screening were used. From this regime, several chemotypes that inhibit Plasmodium mitochondrial electron transport were identified. Excitingly, several new scaffolds, with as-yet-unknown modes of action but solely targeting the parasites' liver stages, emerged as promising drug leads for further development. Science , this issue p. eaat9446 ; see also p. 1112 Screening of more than half a million compounds for their ability to inhibit liver-stage Plasmodium development yields thousands of candidates. To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

Key Points Artemisinin is an antimalarial drug precursor that is produced by the plant Artemisia annua . The supply and price of artemisinin have fluctuated substantially throughout the past decade, owing to inconsistencies in harvest. Artemisinin-based combination therapies (ACTs) are recommended by the WHO as the first-line treatment for uncomplicated malaria. The Semi-synthetic Artemisinin Project aimed to stabilize the supply and price of artemisinin for the development of artemisinin derivatives for use as part of ACTs. Both Escherichia coli and Saccharomyces cerevisiae were engineered using the tools of synthetic biology to produce 25 g per L and 40 g per L, respectively, of the artemisinin hydrocarbon precursor amorphadiene by fermentation. Owing to problems using E. coli , S. cerevisiae was used as the chassis for the industrial-scale production of 25 g per L artemisinic acid by fermentation, which was followed by a chemical conversion process to synthesize artemisinin. Semi-synthetic artemisinin is now produced at industrial scale and has been approved by the WHO for the preparation of approved pharmaceutical compounds for incorporation into ACTs. Lessons learned from the Semi-synthetic Artemisinin Project that are relevant to the development of other pharmaceutical products using metabolic engineering and synthetic biology are summarized. Entry of the antimalarial drug precursor semi-synthetic artemisinin into industrial production is the first major milestone for the application of synthetic biology. In this Review, Paddon and Keasling discuss the metabolic engineering and synthetic biology approaches that were used to engineer Escherichia coli and Saccharomyces cerevisiae to synthesize a precursor of artemisinin, which should aid the development of other pharmaceutical products. Recent developments in synthetic biology, combined with continued progress in systems biology and metabolic engineering, have enabled the engineering of microorganisms to produce heterologous molecules in a manner that was previously unfeasible. The successful synthesis and recent entry of semi-synthetic artemisinin into commercial production is the first demonstration of the potential of synthetic biology for the development and production of pharmaceutical agents. In this Review, we describe the metabolic engineering and synthetic biology approaches that were used to develop this important antimalarial drug precursor. This not only demonstrates the incredible potential of the available technologies but also illuminates how lessons learned from this work could be applied to the production of other pharmaceutical agents.

Rare actinomycetes are prolific in the marine environment; however, knowledge about their diversity, distribution and biochemistry is limited. Marine rare actinomycetes represent a rather untapped source of chemically diverse secondary metabolites and novel bioactive compounds. In this review, we aim to summarize the present knowledge on the isolation, diversity, distribution and natural product discovery of marine rare actinomycetes reported from mid-2013 to 2017. A total of 97 new species, representing 9 novel genera and belonging to 27 families of marine rare actinomycetes have been reported, with the highest numbers of novel isolates from the families Pseudonocardiaceae, Demequinaceae, Micromonosporaceae and Nocardioidaceae. Additionally, this study reviewed 167 new bioactive compounds produced by 58 different rare actinomycete species representing 24 genera. Most of the compounds produced by the marine rare actinomycetes present antibacterial, antifungal, antiparasitic, anticancer or antimalarial activities. The highest numbers of natural products were derived from the genera Nocardiopsis, Micromonospora, Salinispora and Pseudonocardia. Members of the genus Micromonospora were revealed to be the richest source of chemically diverse and unique bioactive natural products.

Tue describes working with investigators on the extraction and isolation of constitutents with possible antimalarial activities from Chinese herbal materials. During the first stage of their work, they investigated more than 2,000 Chinese herb preparations and identified 640 hits that had possible antimalarial activities. More than 380 extracts obtained from ~200 Chinese herbs were evaluated against a mouse model of malaria. The turning point came when an Artemisia annua L. extract showed a promising degree of inhibition against parasite growth.

A decade of discovery and development of new anti-malarial medicines has led to a renewed focus on malaria elimination and eradication. Changes in the way new anti-malarial drugs are discovered and developed have led to a dramatic increase in the number and diversity of new molecules presently in pre-clinical and early clinical development. The twin challenges faced can be summarized by multi-drug resistant malaria from the Greater Mekong Sub-region, and the need to provide simplified medicines. This review lists changes in anti-malarial target candidate and target product profiles over the last 4 years. As well as new medicines to treat disease and prevent transmission, there has been increased focus on the longer term goal of finding new medicines for chemoprotection, potentially with long-acting molecules, or parenteral formulations. Other gaps in the malaria armamentarium, such as drugs to treat severe malaria and endectocides (that kill mosquitoes which feed on people who have taken the drug), are defined here. Ultimately the elimination of malaria requires medicines that are safe and well-tolerated to be used in vulnerable populations: in pregnancy, especially the first trimester, and in those suffering from malnutrition or co-infection with other pathogens. These updates reflect the maturing of an understanding of the key challenges in producing the next generation of medicines to control, eliminate and ultimately eradicate malaria.

The study was planned to screen the marine actinobacterial extract for the protease inhibitor activity and its anti- Pf activity under in vitro and in vivo conditions. Out of 100 isolates, only 3 isolates exhibited moderate to high protease inhibitor activities on trypsin, chymotrypsin and proteinase K. Based on protease inhibitor activity 3 isolates were chosen for further studies. The potential isolate was characterized by polyphasic approach and identified as Streptomyces sp LK3 (JF710608). The lead compound was identified as peptide from Streptomyces sp LK3. The double-reciprocal plot displayed inhibition mode is non-competitive and it confirms the irreversible nature of protease inhibitor. The peptide from Streptomyces sp LK3 extract showed significant anti plasmodial activity (IC50: 25.78 µg/ml). In in vivo model, the highest level of parasitemia suppression (≈ 45%) was observed in 600 mg/kg of the peptide. These analyses revealed no significant changes were observed in the spleen and liver tissue during 8 dpi. The results confirmed up-regulation of TGF-β and down regulation of TNF-α in tissue and serum level in PbA infected peptide treated mice compared to PbA infection. The results obtained infer that the peptide possesses anti- Pf activity activity. It suggests that the extracts have novel metabolites and could be considered as a potential source for drug development.

Key Points Although malaria continues to affect 40% of the world's population and is estimated to be responsible for up to 1 million deaths per year, the number of cases reported by the World Health Organization has declined. Some fear that these advances will be reversed if parasites become resistant to artemisinins, which is currently the only class of antimalarial drug that works effectively against all drug-resistant parasite strains. Ever-slowing response times to artemisinin monotherapies and the risk that these compounds will lose effectiveness over time has spurred the new search for replacement therapies. The World Health Organization and several non-profit, non-governmental organizations have made the elimination of malaria a long-term public health goal. This has generated interest in developing novel antimalarial compounds that can not only eliminate the symptoms of malaria but also remove all parasites from the body and prevent the spread of malaria. In recent years, sophisticated and powerful cellular and phenotypic screening methods have identified drug candidates that are active against different stages of the parasite's life cycle, and at least two of these novel classes of antimalarial drugs are being tested for efficacy in humans. For known, validated antimalarial 'targets', structure-guided drug design has yielded drug candidates that have higher potency and activity against drug-resistant malaria parasites than the drugs that are currently available against these targets. Insightful chemical design has also resulted in new drug candidates that have improved potency or that remain in the patient's bloodstream for a longer period of time. Current antimalarial therapy heavily relies on artemisinins, a drug class that only targets the blood stages of the parasite and which is increasingly feared to elicit drug resistance. Flannery, Chatterjee and Winzeler discuss the approaches used to develop novel drugs that are active against different life cycle stages with the ultimate aim of eliminating malaria. Malaria elimination has recently been reinstated as a global health priority but current therapies seem to be insufficient for the task. Elimination efforts require new drug classes that alleviate symptoms, prevent transmission and provide a radical cure. To develop these next-generation medicines, public–private partnerships are funding innovative approaches to identify compounds that target multiple parasite species at multiple stages of the parasite life cycle. In this Review, we discuss the cell-, chemistry- and target-based approaches used to discover new drug candidates that are currently in clinical trials or undergoing preclinical testing.

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library—many of which showed potent in vitro activity against drug-resistant P. falciparum strains—and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery. Antimalarial arsenal There are still nearly 250 million malaria cases reported annually, over 800,000 fatal, with most deaths being children under 5. The malaria parasite Plasmodium falciparum is notoriously adept at developing drug resistance, and new drugs are urgently needed. Two reports raise hopes that alternatives to artemisinins might be found, by identifying thousands of compounds inhibiting the growth of P. falciparum asexual-stage parasites in red blood cells, many distinct in structure and mechanism from current drugs. Guiguemde et al . present a chemical genomics screen of over 300,000 compounds: the 1,300 'hits' include 561 with good potency and broad therapeutic windows. Gamo et al . screened nearly 2 million compounds from GlaxoSmithKline's chemicals library, finding over 13,500 hits, many active against multidrug-resistant isolates. These studies provide a rich source of potential leads, freely available to academic and industry labs looking for new antimalarials. Here, a library of more than 300,000 chemicals was screened for activity against Plasmodium falciparum growing in red blood cells. Of these chemicals, 172 representative candidates were profiled in detail; one exemplar compound showed efficacy in a mouse model of malaria. The findings provide the scientific community with new starting points for drug discovery.

In the fight against malaria new medicines are an essential weapon. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made: for example combination medicines which allow for single dose regimens, cheaper, safer and more effective medicines, or improved stability under field conditions. For those parts of the world where the existing combinations show less than optimal activity, the priority is to have activity against emerging resistant strains, and other criteria take a secondary role. For new medicines to be optimal in malaria control they must also be able to reduce transmission and prevent relapse of dormant forms: additional constraints on a combination medicine. In the absence of a highly effective vaccine, new medicines are also needed to protect patient populations. In this paper, an outline definition of the ideal and minimally acceptable characteristics of the types of clinical candidate molecule which are needed (target candidate profiles) is suggested. In addition, the optimal and minimally acceptable characteristics of combination medicines are outlined (target product profiles). MMV presents now a suggested framework for combining the new candidates to produce the new medicines. Sustained investment over the next decade in discovery and development of new molecules is essential to enable the long-term delivery of the medicines needed to combat malaria.