Determining the pharmacological potential and biological role of linear pseudoscorpion toxins via functional profiling.

Arthropod venoms contain bioactive molecules attractive for biomedical applications. However, few of these have been isolated, and only a tiny number has been characterized. Pseudoscorpions are small arachnids whose venom has been largely overlooked. Here, we present the first structural and functional assessment of the checacin toxin family, discovered in the venom of the house pseudoscorpion (Chelifer cancroides). We combined in silico and in vitro analyses to establish their bioactivity profile against microbes and various cell lines. This revealed inhibitory effects against bacteria and fungi. We observed cytotoxicity against specific cell types and effects involving second messengers. Our work provides insight into the biomedical potential and evolution of pseudoscorpion venoms. We propose that plesiotypic checacins evolved to defend the venom gland against infection, whereas apotypic descendants evolved additional functions. Our work highlights the importance of considering small and neglected species in biodiscovery programs.

5'-Methoxyarmillane, a Bioactive Sesquiterpenoid Aryl Ester from the Fungus Armillaria ostoyae.

Higher fungi of the genus Armillaria belonging to the phylum Basidiomycota produce bioactive sesquiterpenoid aryl esters called melleolides. A bioactivity-guided discovery process led to the identification of the new melleolide 5'­methoxyarmillane (1) in organic extracts from the mycelium of Armillaria ostoyae. Remarkably, supplementation of rapeseed oil to the culture medium potato dextrose broth increased the production of 1 by a factor of six during the course of the 35 days fermentation. Compound 1 was isolated and its structure elucidated by UHPLC-QTOF-HR-MS/MS and NMR spectroscopy. It showed toxicity against Madin-Darby canine kidney II (MDCK II, IC50 19.2 mg/mL, 44.1 mM) and human lung cancer Calu-3 cells (IC50 15.2 mg/mL, 34.9 mM) as well as moderate bioactivity against Mycobacterium tuberculosis (MIC 8 mg/mL, 18.4 mM) and Mycobacterium smegmatis (MIC 16 mg/mL, 36.8 mM), but not against Staphylococcus aureus, Escherichia coli, Candida albicans, and Septoria tritici. No inhibitory effects of 1 against the influenza viruses H3N2, H1N1pdm, B/Malaysia, and B/Massachusetts were observed.

Physiochemical interaction between osmotic stress and a bacterial exometabolite promotes plant disease.

Various microbes isolated from healthy plants are detrimental under laboratory conditions, indicating the existence of molecular mechanisms preventing disease in nature. Here, we demonstrated that application of sodium chloride (NaCl) in natural and gnotobiotic soil systems is sufficient to induce plant disease caused by an otherwise non-pathogenic root-derived Pseudomonas brassicacearum isolate (R401). Disease caused by combinatorial treatment of NaCl and R401 triggered extensive, root-specific transcriptional reprogramming that did not involve down-regulation of host innate immune genes, nor dampening of ROS-mediated immunity. Instead, we identified and structurally characterized the R401 lipopeptide brassicapeptin A as necessary and sufficient to promote disease on salt-treated plants. Brassicapeptin A production is salt-inducible, promotes root colonization and transitions R401 from being beneficial to being detrimental on salt-treated plants by disturbing host ion homeostasis, thereby bolstering susceptibility to osmolytes. We conclude that the interaction between a global change stressor and a single exometabolite from a member of the root microbiome promotes plant disease in complex soil systems.

Design, synthesis and antimycobacterial activity of imidazo[1,5-a]quinolines and their zinc-complexes.

Tuberculosis has remained one of the world's deadliest infectious diseases. The complexity and numerous adverse effects of current treatment options as well as the emergence of multi-drug resistant M. tuberculosis (Mtb) demand research and innovation efforts to yield new anti-mycobacterial agents. In this study, we synthesized a series of imidazo[1,5-a]quinolines, including 4 new analogs, and evaluated their activity against Mtb. Inspired by previous studies, we also designed 8 compounds featuring a coordinated metal ion, determined their absolute configuration by single-crystal X-ray diffraction and included them in the bioactivity study. Remarkably, the metal complexation of 5c with either Zn2+ or Fe2+ increased the Mtb inhibitory activity of the compound 12.5-fold and reduced its cytotoxicity. Ultimately, out of the 21 analyzed imidazo[1,5-a]quinoline analogs, two zinc complexes (C1 and C7) showed the strongest, specific activity against Mtb H37Rv in vitro (IC90 = 7.7 and 17.7 µM).