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Steadily increasing antifungal drug resistance and persistent high rates of fungal-associated mortality highlight the dire need for the development of novel antifungals. Characterization of inhibitors of one enzyme in the GPI anchor pathway, Gwt1, has generated interest in the exploration of targets in this pathway for further study. Utilizing a chemical genomics-based screening platform referred to as the Candida albicans fitness test (CaFT), we have identified novel inhibitors of Gwt1 and a second enzyme in the glycosylphosphatidylinositol (GPI) cell wall anchor pathway, Mcd4. We further validate these targets using the model fungal organism Saccharomyces cerevisiae and demonstrate the utility of using the facile toolbox that has been compiled in this species to further explore target specific biology. Using these compounds as probes, we demonstrate that inhibition of Mcd4 as well as Gwt1 blocks the growth of a broad spectrum of fungal pathogens and exposes key elicitors of pathogen recognition. Interestingly, a strong chemical synergy is also observed by combining Gwt1 and Mcd4 inhibitors, mirroring the demonstrated synthetic lethality of combining conditional mutants of GWT1 and MCD4. We further demonstrate that the Mcd4 inhibitor M720 is efficacious in a murine infection model of systemic candidiasis. Our results establish Mcd4 as a promising antifungal target and confirm the GPI cell wall anchor synthesis pathway as a promising antifungal target area by demonstrating that effects of inhibiting it are more general than previously recognized., Genome Canada (Firm), Genome Quebec

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products

Oleoylethanolamide (OEA) is a bioactive lipid mediator, produced in the intestine and other tissues, which is involved in energy balance regulation in mammals, modulating feeding and lipid metabolism. The purpose of the present study was to investigate the presence and possible role of OEA in feeding regulation in goldfish (Carassius auratus). We assessed whether goldfish peripheral tissues and brain contain OEA and their regulation by nutritional status. OEA was detected in all studied tissues (liver, intestinal bulb, proximal intestine, muscle, hypothalamus, telencephalon and brainstem). Food deprivation (48 h) reduced intestinal OEA levels and levels increased upon re-feeding, suggesting that this compound may be involved in the short-term regulation of food intake in goldfish, as a satiety factor. Next, the effects of acute intraperitoneal administration of OEA on feeding, swimming and plasma levels of glucose and triglycerides were analysed. Food intake, swimming activity and circulating triglyceride levels were reduced by OEA 2 h post-injection. Finally, the possible interplay among OEA and other feeding regulators (leptin, cholecystokinin, ghrelin, neuropeptide Y, orexin and monoamines) was investigated. OEA actions on energy homeostasis in goldfish could be mediated, at least in part, through interactions with ghrelin and the serotonergic system, as OEA treatment reduced ghrelin expression in the intestinal bulb, and increased serotonergic activity in the telencephalon. In summary, our results indicate for the first time in fish that OEA could be involved in the regulation of feeding, swimming and lipid metabolism, suggesting a high conservation of OEA actions in energy balance throughout vertebrate evolution.

Oleoylethanolamide (OEA) is a bioactive lipid mediator, produced in the intestine and other tissues, which is involved in energy balance regulation in mammals, modulating feeding and lipid metabolism. The purpose of the present study was to investigate the presence and possible role of OEA in feeding regulation in goldfish (Carassius auratus). We assessed whether goldfish peripheral tissues and brain contain OEA and their regulation by nutritional status. OEA was detected in all studied tissues (liver, intestinal bulb, proximal intestine, muscle, hypothalamus, telencephalon and brainstem). Food deprivation (48 h) reduced intestinal OEA levels and levels increased upon re-feeding, suggesting that this compound may be involved in the short-term regulation of food intake in goldfish, as a satiety factor. Next, the effects of acute intraperitoneal administration of OEA on feeding, swimming and plasma levels of glucose and triglycerides were analysed. Food intake, swimming activity and circulating triglyceride levels were reduced by OEA 2 h post-injection. Finally, the possible interplay among OEA and other feeding regulators (leptin, cholecystokinin, ghrelin, neuropeptide Y, orexin and monoamines) was investigated. OEA actions on energy homeostasis in goldfish could be mediated, at least in part, through interactions with ghrelin and the serotonergic system, as OEA treatment reduced ghrelin expression in the intestinal bulb, and increased serotonergic activity in the telencephalon. In summary, our results indicate for the first time in fish that OEA could be involved in the regulation of feeding, swimming and lipid metabolism, suggesting a high conservation of OEA actions in energy balance throughout vertebrate evolution.

[EN] Trichothecene mycotoxins are recognized as highly bioactive compounds that can be used in the design of new useful bioactive molecules. In Trichoderma brevicompactum, the first specific step in trichothecene biosynthesis is carried out by a terpene cyclase, trichodiene synthase, that catalyzes the conversion of farnesyl diphosphate to trichodiene and is encoded by the tri5 gene. Overexpression of tri5 resulted in increased levels of trichodermin, a trichothecene-type toxin, which is a valuable tool in preparing new molecules with a trichothecene skeleton. In this work, we developed the hemisynthesis of trichodermin and trichodermol derivatives in order to evaluate their antimicrobial and cytotoxic activities and to study the chemo-modulation of their bioactivity. Some derivatives with a short chain at the C-4 position displayed selective antimicrobial activity against Candida albicans and they showed MIC values similar to those displayed by trichodermin. It is important to highlight the cytotoxic selectivity observed for compounds 9, 13, and 15, which presented average IC50 values of 2 µg/mL and were cytotoxic against tumorigenic cell line MCF-7 (breast carcinoma) and not against Fa2N4 (non-tumoral immortalized human hepatocytes)