Comprehensive prediction of secondary metabolite structure and biological activity from microbial genome sequences.

Novel antibiotics are urgently needed to address the looming global crisis of antibiotic resistance. Historically, the primary source of clinically used antibiotics has been microbial secondary metabolism. Microbial genome sequencing has revealed a plethora of uncharacterized natural antibiotics that remain to be discovered. However, the isolation of these molecules is hindered by the challenge of linking sequence information to the chemical structures of the encoded molecules. Here, we present PRISM 4, a comprehensive platform for prediction of the chemical structures of genomically encoded antibiotics, including all classes of bacterial antibiotics currently in clinical use. The accuracy of chemical structure prediction enables the development of machine-learning methods to predict the likely biological activity of encoded molecules. We apply PRISM 4 to chart secondary metabolite biosynthesis in a collection of over 10,000 bacterial genomes from both cultured isolates and metagenomic datasets, revealing thousands of encoded antibiotics. PRISM 4 is freely available as an interactive web application at http://prism.adapsyn.com .

Characterization of multimeric daptomycin bound to lipid nanodiscs formed by calcium-tolerant styrene-maleic acid copolymer.

Daptomycin is a lipopeptide antibiotic that is important in the treatment of infections with Gram-positive bacteria. In the presence of calcium, daptomycin binds to phosphatidylglycerol in the bacterial cytoplasmic membrane and then forms oligomers that mediate its bactericidal effect. The structure of these bactericidal oligomers has not been elucidated. We here explore the feasibility of structural studies on the oligomer by solution-state NMR. To this end, we use nanodiscs that contain DMPC and DMPG, stabilized with a styrene-maleic acid copolymer that has been modified to minimize calcium chelation. We show that these nanodiscs bind daptomycin and induce the formation of stable oligomers under physiologically relevant conditions. The findings suggest that this membrane model is suitable for structural and functional characterization of oligomeric daptomycin, and possibly of other calcium-dependent lipopeptide antibiotics. We show that these nanodiscs bind daptomycin and induce the formation of stable oligomers, under conditions that are suitable for biomolecular NMR. The findings suggest that this membrane model is suitable for structural elucidation of oligomeric daptomycin, and possibly of other calcium-dependent lipopeptide antibiotics.

Evaluation of mean transit time of aerosols from the area of origin to the Arctic with 210Pb/210Po daily monitoring data.

In this study, the activity concentrations of 210Pb and 210Po on the 22 daily air filter samples, collected at CTBT Yellowknife station from September 2015 to April 2016, were analysed. To estimate the time scale of atmospheric long-range transport aerosol bearing 210Pb in the Arctic during winter, the mean transit time of aerosol bearing 210Pb from its origin was determined based on the activity ratios of 210Po/210Pb and the parent-progeny decay/ingrowth equation. The activity ratios of 210Po/210Pb varied between 0.06 and 0.21 with a median value of 0.11. The aerosol mean transit time based the activity ratio of 210Po/210Pb suggests longer mean transit time of 210Pb aerosols in winter (12 d) than in autumn (3.7 d) and spring (2.9 d). Four years 210Pb and 212Pb monitoring results and meteorological conditions at the Yellowknife station indicate that the 212Pb activity is mostly of local origin, and that 210Pb aerosol in wintertime are mainly from outside of the Arctic regions in common with other pollutants and sources contributing to the Arctic. The activity concentration ratios of 210Pb and 212Pb have a relatively constant value in summer with a significant peak observed in winter, centered in the month of February. Comparison of the 210Pb/212Pb activity ratios and the estimated mean 210Pb transit time, the mean aerosol transit times were real reflection of the atmosphere transport characteristics, which can be used as a radio-chronometer for the transport of air masses to the Arctic region.