How Microbes Make Drug-like Molecules

An anti-HIV peptide obtained by mining the animal microbiome.

Many life-saving drugs come from natural sources such as microbes. Learning how host organisms produce these drugs is an area of intense interest because scientists could exploit the pathways to produce more and better drug variants. Schmidt and colleagues have elucidated the mechanisms by which microbes produce one class of drug-like molecules, the Ribosomally-synthesized and Post-translationally modified Peptides (RiPPs). Bioactive RiPPs are produced from a precursor peptide, which is modified by enzymes.

The research group identified specific biosynthetic pathways that produce such discrete natural product compounds, which have potential as human therapeutics. These discoveries demonstrate how modern metagenomic methods can elucidate the vast repertoire of natural products that were inaccessible using traditional isolation methods. The insights now influence how other investigators in the natural products field tailor their investigations to discover novel drugs as potential lead therapeutics.


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Metabolic model for diversity-generating biosynthesis. Tianero MD, Pierce E, Raghuraman S, Sardar D, McIntosh JA, Heemstra JR, Schonrock Z, Covington BC, Maschek JA, Cox JE, Bachmann BO, Olivera BM, Ruffner DE, Schmidt EW. Proc Natl Acad Sci USA. 2016 Feb;113(7):1772.

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Accessing chemical diversity from the uncultivated symbionts of small marine animals. Smith TE, Pond CD, Pierce E, Harmer ZP, Kwan J, Zachariah MM, Harper MK, Wyche TP, Matainaho TK, Bugni TS, Barrows LR, Ireland CM, Schmidt EW. Nat Chem Biol. 2018 Feb;14(2):179.

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The biosynthetic diversity of the animal world. Torres JP, Schmidt EW. J Biol Chem. 2019 Nov;294(46):17684.