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Studies on new phosphonic acid antibiotics. Iguchi, E., Okuhara, M., Kohsaka, M., Aoki, H. Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes. A roadmap for natural product discovery based on large-scale genomics and metabolomics. Natural products as sources of new drugs from 1981 to 2014. ‘Superweeds’ or ‘survivors’? Framing the problem of glyphosate resistant weeds and genetically engineered crops. World Malaria Report 2016 (World Health Organization, 2016).īain, C., Selfa, T., Dandachi, T. The required genes and biosynthetic pathway for dehydrofosmidomycin differ substantially from that of the related natural product FR-900098, suggesting that the ability to produce these bioactive molecules arose via convergent evolution.Īntibiotic Resistance Threats in the United States, Antibiotic/Antimicrobial Resistance (The Centers for Disease Control and Prevention, 2013). Bioinformatics analyses, characterization of intermediates and in vitro biochemistry show that the biosynthetic pathway involves conversion of a two-carbon phosphonate precursor into the unsaturated three-carbon product via a highly unusual rearrangement reaction, catalyzed by the 2-oxoglutarate dependent dioxygenase DfmD. The genes required for dehydrofosmidomycin biosynthesis were established by heterologous expression experiments.
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We were unable to elicit production of fosmidomycin, instead observing the unsaturated derivative dehydrofosmidomycin, which we showed potently inhibits 1-deoxy- d-xylulose-5-phosphate reductoisomerase and has bioactivity against a number of bacteria. To understand the biosynthesis of these compounds, we characterized the fosmidomycin producer, Streptomyces lavendulae, using biochemical and genetic approaches. Fosmidomycin and related molecules comprise a family of phosphonate natural products with potent antibacterial, antimalarial and herbicidal activities.