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Our previous study identified 52 antiplasmodial peptaibols isolated from fungi. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays, assessed the in vitro evolution of resistance, and performed a transcriptome analysis of the most potent peptaibol, HZ NPDG-I. HZ NPDG-I and 2 additional peptaibols were compared for their killing action and stage dependency, each showing a loss of digestive vacuole (DV) content via ultrastructural analysis. HZ NPDG-I demonstrated a stepwise increase in DV pH, impaired DV membrane permeability, and the ability to form ion channels upon reconstitution in planar membranes. This compound showed no signs of cross resistance to targets of current clinical candidates, and 3 independent lines evolved to resist HZ NPDG-I acquired nonsynonymous changes in the P. falciparum multidrug resistance transporter, pfmdr1. Conditional knockdown of PfMDR1 showed varying effects to other peptaibol analogs, suggesting differing sensitivity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study aimed to compare the efficacy of two pharmacological protocols for inducing ex copula ejaculation in donkeys. Seven healthy jacks (male donkeys) aged 4 to 20 years (median 8 years) and weighing 136.2±4.17 kg (mean±SE) were enrolled. Using a crossover design, each jack was subjected in a random order to two treatment protocols (IX and IDO) with an interval of 7 days between the two protocols. Each jack was orally administered 3 mg/kg imipramine hydrochloride followed 2 hours later by intravenous (IV) administration of 1.1 mg/kg xylazine hydrochloride (IX protocol) or 0.02 mg/kg detomidine hydrochloride and 20 IU total dose oxytocin (IDO protocol). The jacks were monitored for behavioral changes and ejaculation up to 3 hours from the beginning of each protocol. A total of 22 ex copula ejaculation replicates were attempted. Both protocols resulted in deep sedation and partial to complete penile protrusion in all jacks. There was no difference in the efficacy with the IX protocol inducing ejaculation in 1 of the 11 replicates and the IDO protocol inducing ejaculation in none of the 11 replicates. The results suggest that neither of the two tested pharmacological protocols were effective in inducing ex copula ejaculation in donkeys., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Identifying how small molecules act to kill malaria parasites can lead to new "chemically validated" targets. By pressuring Plasmodium falciparum asexual blood stage parasites with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), and performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. falciparum acyl-CoA synthetase (ACS) genes PfACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and PfACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates PfACS10 as a target of these compounds. We demonstrate that this protein is essential for parasite growth by conditional knockdown and observe increased compound susceptibility upon reduced expression. Inhibition of PfACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the PfACS11 gene and its mutations point to a role in mediating resistance via decreased protein stability., (© 2023. The Author(s).)