Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway.

A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZP-resistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing

Parasite attractants: identifying trap baits for parasite management in aquaculture

Aquatic parasites may respond to various attractants and cues to find and infect a host. Traps that use these attractants as 'bait' have potential to reduce the number of pathogenic agents in aquaculture environments. This study examined four potential attractants (i.e., urea, host mucus, parasite conspecifics and light) and the response of two problematic marine parasite species, to identify the most suitable bait for trap development in finfish aquaculture. Two globally distributed parasite species (i.e., Neobenedenia girellae, (Hargis, 1955); and Cryptocaryon irritans, Brown, 1951) were chosen as models. A chemotaxis experiment was used to compare the attractiveness of each species' infectious life stage to urea, host mucus, parasite conspecifics and a seawater control, while a phototaxis experiment was used to identify phototactic responses of the parasites to light or dark. We found that urea and light attracted more than twice the number of infective protozoans and flukes (monogeneans), respectively, compared to other attractants/controls. Cryptocaryon irritans theronts were positively chemotactic to urea (Beta Regression Analysis; Odds Ratio (OR) 2.69, p = 0.00017), while Neobendenia girellae was positively phototactic to light (Mixed Effect Logistic Regression; OR 2.5, p = 0.0014). A final experiment examined the emergence of C. irritans over a 24-hour period and identified that the vast majority excysted at night (ANOVA; p-value < 0.001). In contrast, previous studies have shown that the majority of N. girellae oncomiracidia hatch in the morning. This indicated that the best time to deploy traps to capture infective C. irritans theronts and N. girellae oncomiracidia would be prior to sunset and sunrise, respectively. The manipulation of urea and light and other potential attractants combined with strategic deployment of traps to coincide with the emergence of infectious life stages may prove useful in aquaculture where parasite epidemics can compromise production and animal welfare