Editorial: natural products themed issue

With their unsurpassed structural diversity as well as their numerous and various biological functions and activities, it is not surprising that natural products have been, and continue to be, at the forefront of the drug discovery process. Natural products derived from all life forms have been a continuous source of motivation for scientists from a variety of disciplines, including biochemistry, biology, biophysics, bioinformatics, chemistry, and microbiology. Natural products can be divided into two categories: (i) those built on multi-modular enzymatic machineries that encompass fatty acids (FAs), nonribosomal peptides, polyketides, and their hybrids, and (ii) the non-templated natural products that include alkaloids, aminoglycosides, phosphonates, oligosaccharides, and lantibiotics. Overall, the study of these small molecules has led to a better understanding of nature's intricate mechanisms and functions, the identification of novel drug targets, the development of new synthetic and biosynthetic processes, the engineering and repurposing of enzymes as biocatalysts and tools for production of unnatural “natural” products, as well as the advancement of new computational and biophysical methods.

In this MedChemComm natural products themed issue, teams of natural product experts from around the world share with the readers their valuable insight and perspective as well as their latest discoveries in this thriving area of research. This themed issue features a combination of twenty-three reviews and concise articles that are intended to lead the readers through a unique journey towards gaining knowledge about some of the important multiple facets of the study and development of natural products as potential drugs.

The nine reviews contained in this issue elegantly summarize the synthesis, biosynthesis, inhibitory properties and targets, and biological functions of natural products, as well as new bioinformatics methods for their identification. Koehn provides a thorough overview of the biosynthetic medicinal chemistry of natural product drugs (10.1039/C2MD00316C), whereas Bowers contributes an in-depth analysis of the biochemical and biosynthetic preparation of natural product-like cyclic peptide libraries (10.1039/C2MD20068F). Musiol and Weber introduce the world of polyketides with a comprehensive report on the discrete acyltransferases involved in their biosynthesis (10.1039/C2MD20048A). Mann and Peters summarize findings of a unique natural product of Mycobacterium tuberculosis with a new physiological role of medical relevance (10.1039/C2MD20030A). Wakimoto and Abe cover in a thoughtful review the current successes in isolating labile natural products (10.1039/C2MD20016C). Magarvey and co-workers present state of the art informatic search strategies for polyketide and nonribosomal peptide natural product discovery (10.1039/C2MD20120H). Finally, three insightful reviews by Khosla and co-workers (10.1039/C2MD20008B), Agarwal and Nair (10.1039/C2MD20032E), as well as Tan and Romesberg (10.1039/C2MD20043K) describing the inhibitory activities of natural products against new interesting targets demonstrate the plethora of potential directions in the study of these small molecules.

This themed issue also features fourteen concise articles describing some of the newest discoveries in the field of natural products. Three research articles focus on novel natural product biosynthetic gene clusters. Sherman, Williams, and co-workers present a thorough comparative analysis of biosynthetic systems for fungal alkaloids (10.1039/C2MD20029E). Wang and co-workers nicely complement the above study with the identification and molecular genetic analysis of the phytotoxin cichorine gene cluster from the filamentous fungi Aspergillus nidulans (10.1039/C2MD20055D). In their fascinating manuscript, Wright and co-workers reveal the biosynthetic gene cluster and exciting antimicrobial activity of the antibiotic factumycin (10.1039/C2MD20038D). Three additional manuscripts provide insight into new biosynthetic transformations. Zolova and Garneau-Tsodikova show the importance of an MbtH-like protein for the production of the antitumor agent thiocoraline (10.1039/C2MD20131C). van der Donk and co-workers nicely demonstrate the stereochemistry of hydride transfer from NADPH to phosphonoacetaldehyde by group III alcohol dehydrogenases during phosphonate biosynthesis (10.1039/C2MD20009K). Du, Shen, and co-workers explore the 3-hydroxylation of the polycyclic tetramate macrolactam in the biosynthesis of an antifungal agent (10.1039/C2MD20026K). To expand the utility and potential of enzymes involved in natural product biosynthesis for development of novel natural product analogues, Townsend and co-workers cleverly engineer β-lactam synthetases (10.1039/C2MD00305H), whereas Keatinge-Clay and co-workers employ the polyketide synthase and thioesterase enzymes as biocatalysts in the semi-preparative formation of triketide pyrones (10.1039/C2MD20013A). Two other articles show the elegant chemical synthesis of natural products. Vederas and co-workers present the solid phase supported peptide synthesis of lantibiotics (10.1039/C2MD20014G), whereas Brimble and co-workers describe the chemical synthesis and activity of spirolaxine methyl ether analogues (10.1039/C2MD00314G). The inhibitory power of natural products is exemplified in three articles. Gregory and co-workers present the sangamides as a new class of cyclophilin-inhibiting host-targeted antivirals (10.1039/C2MD00227A). Cheng and co-workers reveal the thailandepsins as potent histone deacetylase inhibitors. Campopiano and co-workers establish the mechanism of serine palmitoyltransferase inhibition by L-penicillamine (10.1039/C2MD20024D). Finally, Heide and co-workers reveal a novel mechanism of resistance against phenazines (10.1039/C2MD20045G).

From the combined articles presented in this themed issue, it is clear that the field of natural products is ever growing and expanding in many new directions. We hope that the readers of MedChemComm, experts or new to this amazing field of research, will enjoy this collection of manuscripts and find in it inspiration for their own work.

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