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. Malaria leads to the loss of over 440,000 lives annually; accelerating research to discover new candidate drugs is a priority. Medicines for Malaria Venture (MMV) has distilled over 25,000 compounds that kill malaria parasites in vitro into a group of 400 representative compounds, called the "Malaria Box". These Malaria Box sets were distributed free-of-charge to research laboratories in 30 different countries that work on a wide variety of pathogens. Fifty-five groups compiled >290 assay results for this paper describing the many activities of the Malaria Box compounds. The collective results suggest a potential mechanism of action for over 130 compounds against malaria and illuminate the most promising compounds for further malaria drug development research. Excitingly some of these compounds also showed outstanding activity against other disease agents including fungi, bacteria, other single-cellular parasites, worms, and even human cancer cells. The results have ignited over 30 drug development programs for a variety of diseases. This open access effort was so successful that MMV has begun to distribute another set of compounds with initial activity against a wider range of infectious agents that are of public health concern, called the Pathogen Box, available now to scientific labs all over the world (www.PathogenBox.org).

The search for novel therapeutic options to cure alveolar echinococcosis (AE), due to the metacestode of Echinococcus multilocularis, is ongoing, and these developments could also have a profound impact on the treatment of cystic echinococcosis (CE), caused by the closely related Echinococcus granulosus s.l. Several options are being explored. A viable strategy for the identification of novel chemotherapeutically valuable compounds includes whole-organism drug screening, employing large-scale in vitro metacestode cultures and, upon identification of promising compounds, verification of drug efficacy in small laboratory animals. Clearly, the current focus is targeted towards broad-spectrum anti-parasitic or anti-cancer drugs and compound classes that are already marketed, or that are in development for other applications. The availability of comprehensive Echinococcus genome information and gene expression data, as well as significant progress on the molecular level, has now opened the door for a more targeted drug discovery approach, which allows exploitation of defined pathways and enzymes that are essential for the parasite. In addition, current in vitro and in vivo models that are used to assess drug efficacy should be optimized and complemented by methods that give more detailed information on the host-parasite interactions that occur during drug treatments. The key to success is to identify, target and exploit those parasite molecules that orchestrate activities essential to parasite survival. La recherche de nouvelles options thérapeutiques curatives de l’échinococcose alvéolaire (EA), due au métacestode d’Echinococcus multilocularis, est en progrès, et ses développements pourraient aussi avoir un profond impact sur le traitement de l’échinococcose kystique (EK), due au cestode très proche Echinococcus granulosus s.l. Plusieurs options sont explorées. Une stratégie efficace pour l’identification de composés nouveaux à activité chimiothérapique est représentée par le criblage de médicaments sur le micro-organisme entier, utilisant des cultures à grande échelle de métacestodes in vitro et, après identification de composés d’intérêt, la vérification de leur activité chez des animaux de laboratoire. La recherche actuelle est clairement centrée sur les médicaments et les classes de substances à activité antiparasitaire et anti-cancéreuse à large spectre qui sont déjà sur le marché ou en cours de développement dans d’autres applications. La mise à disposition d’informations complètes sur le génome d’Echinococcus et sur l’expression des gènes ainsi que des progrès significatifs à l’échelle moléculaire ouvrent maintenant la porte vers une approche plus ciblée pour la découverte de nouveaux médicaments, en permettant l’exploitation de voies métaboliques et d’enzymes indispensables au parasite. De plus, les modèles actuels, in vitro et in vivo, actuellement utilisés pour confirmer l’efficacité d’un médicament, devraient être optimisés et complétés par des méthodes qui permettraient d’obtenir des informations plus détaillés sur les relations hôte-parasite qui surviennent au cours des traitements. La clé du succès est d’identifier, de cibler et d’exploiter les molécules parasitaires qui orchestrent des activités essentielles à la survie du parasite.

Key features: Written by the scientist who named this parasite and was the first to set up proper diagnostic techniques Serves as the first ever book to provide information on the parasite structure, biology, pathogenesis, clinical signs, epidemiology, prevention, and control of neosporosis Covers both approaches toward preventing & controlling this disease: Developing an efficacious vaccine and sound cattle management practices Contains a wealth of illustrations, including many of the author's original photographs of the parasite Provides basic information on immunologic and molecular aspects of the disease Abortion is a worldwide problem in the livestock industry accounting for annual economic losses of billions of dollars, and N. caninum is a major cause of it. Neosporosis is a newly recognized disease of animals. Until 1988 it was misdiagnosed as toxoplasmosis. Considerable progress in understanding the biology of neosporosis has been made in the last 30 years, resulting in more than 2,000 scientific publications. The economic importance of abortion in cattle, and the availability of knowledge, reagents, and technology used to study toxoplasmosis, have contributed to the rapid progress in understanding the biology of neosporosis. Written by pioneers in this field, Neosporosis in Animals presents a comprehensive summary of the biology of neosporosis, starting with chapter 1 on the historical background of the discovery of the disease. Subsequent chapters deal with general aspects of the biology of N. caninum (chapter 2), techniques (chapter 3), and the disease caused by this parasite in cattle (chapter 4), dogs (chapter 5), and all other animals including sheep, pigs, primates and humans (chapters 6-18). This book provides, for the first time in a single authoritative source, a complete account of the structure, biology, clinical disease, diagnosis, epidemiology, treatment, attempts at immunoprophylaxis, and control in all hosts. There are 175 illustrations and tables devoted to the life cycle, structure of parasitic stages, and lesions. More than 2100 references are cited, allowing the reader to locate additional information on specific topics in an efficient way. This book will be useful to a broad range of researchers in biology and veterinarians.

Cyclic nucleotide specific phosphodiesterases (PDEs) are pivotal regulators of cellular signaling. They are also important drug targets. Besides catalytic activity and substrate specificity, their subcel‐lular localization and interaction with other cell components are also functionally important. In contrast to the mammalian PDEs, the significance of PDEs in protozoal pathogens remains mostly unknown. The genome of Trypanosoma brucei , the causative agent of human sleeping sickness, codes for five different PDEs. Two of these, TbrPDEBl and TbrPDEB2, are closely similar, cAMP‐specific PDEs containing two GAF‐do‐mains in their N‐terminal regions. Despite their similarity, these two PDEs exhibit different subcellular localizations. TbrPDEB1 is located in the flagellum, whereas TbrPDEB2 is distributed between flagellum and cytoplasm. RNAi against the two mRNAs revealed that the two enzymes can complement each other but that a simultaneous ablation of both leads to cell death in bloodstream form trypanosomes. RNAi against Tbr‐PDEB1 and TbrPDEB2 also functions in vivo where it completely prevents infection and eliminates ongoing infections. Our data demonstrate that TbrPDEB1 and TbrPDEB2 are essential for virulence, making them valuable potential targets for new PDE‐inhibitor based trypanocidal drugs. Furthermore, they are compatible with the notion that the flagellum of T. brucei is an important site of cAMP signaling.—Oberholzer, M., Marti, G., Baresic, M., Kunz, S., Hemphill, A., Seebeck, T. The Trypanosoma brucei cAMP phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar enzymes that are essential for parasite virulence. FASEB J. 21, 720–731 (2007)

Colonisation of the gastrointestinal tract by anaerobic bacteria, protozoa, trematodes, cestodes and/or nematodes and other infectious pathogens, including viruses, represents a major cause of morbidity and mortality in Africa, South America and southeast Asia, as well as other parts of the world. Nitazoxanide is a member of the thiazolide class of drugs with a documented broad spectrum of activity against parasites and anaerobic bacteria. Moreover, the drug has recently been reported to have a profound activity against hepatitis C virus infection. In addition, nitazoxanide exhibits anti-inflammatory properties, which have prompted clinical investigations for its use in Crohn’s disease. Studies with nitazoxanide derivatives have determined that there must be significantly different mechanisms of action acting on intracellular versus extracellular pathogens. An impressive number of clinical studies have shown that the drug has an excellent bioavailability in the gastrointestinal tract, is fast acting and h...