HSQC-TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates.

Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides.

1H NMR-based metabolomics reveals sub-lethal toxicity of a mixture of diabetic and lipid-regulating pharmaceuticals on amphibian larvae.

Pharmaceuticals are widely used for the treatment of various physical and psychological ailments. Due to incomplete removal during sewage treatment many pharmaceuticals are frequently detected in aquatic waterways at trace concentrations. The diversity of pharmaceutical contaminants and potential for complex mixtures to occur makes it very difficult to predict the toxicity of these compounds on wildlife, and robust methods are therefore needed to explore sub-lethal effects. Metabolic syndrome is one of the most widespread health concerns currently facing the human population, and various drugs, including anti-diabetic medications and lipid- and cholesterol-lowering fibrates and statins, are widely prescribed as treatment. In this study, we exposed striped marsh frog (Limnodynastes peronii) tadpoles to a mixture of the drugs metformin, atorvastatin and bezafibrate at 0.5, 5, 50 and 500µg/L to explore possible effects on growth and development, energy reserves (triglycerides and cholesterol), and profiles of small polar metabolites extracted from hepatic tissues. It was hypothesised that exposure would result in a general reduction in energy reserves, and that this would subsequently correspond with reduced growth and development. Responses differed from expected outcomes based on the known mechanisms of these compounds in humans, with no changes to hepatic triglycerides or cholesterol and a general increase in mass and condition with increasing exposure concentration. Deviation from the expected response patterns may be explained by differences in the receptivity or uptake of the compounds in non-mammalian species. Proton nuclear magnetic resonance (1H NMR) spectroscopy revealed evidence of broad metabolic dysregulation in exposed animals, and possible interaction between the solvent and mixture. Specifically, increased lactic acid and branched-chain amino acids were observed, with responses tending to follow a non-monotonic pattern. Overall, results demonstrate that a mixture of drugs commonly prescribed to treat human metabolic syndrome is capable of eliciting physiological and developmental effects on larval amphibians. Importantly, outcomes further suggest that it may not be possible to predict toxicological effects in non-target wildlife based on our knowledge of how these compounds act in humans.

Chemical and Biological Aspects of Marine Sponges from the Family Mycalidae.

Sponges are a useful source of bioactive natural products. Members of the family Mycalidae, in particular, have provided a variety of chemical structures including alkaloids, polyketides, terpene endoperoxides, peptides, and lipids. This review highlights the compounds isolated from Mycalid sponges and their associated biological activities. A diverse group of 190 compounds have been reported from over 40 specimens contained in 49 references. Over half of the studies have reported on the biological activities for the compounds isolated. The polyketides, in particular the macrolides, displayed potent cytotoxic activities (< 1 µM), and the alkaloids, in particular the 2,5-disubstituted pyrrole derivatives, were associated with moderate cytotoxic activities (1-20 µM). The pyrrole alkaloids and the cyclic peroxides appear to be phylogenetically restricted to sponges and thus might prove useful when applied to sponge taxonomy. The observed diversity of chemical structures suggests this family makes a good target for targeted biodiscovery projects.