Mining the Metabiome: Identifying Novel Natural Products from Microbial Communities

Abstract

Summary Microbial-derived natural products provide the foundation for most of the chemotherapeutic arsenal available to contemporary medicine. In the face of a dwindling pipeline of new lead structures identified by traditional culturing techniques and an increasing need for new therapeutics, surveys of microbial biosynthetic diversity across environmental metabiomes have revealed enormous reservoirs of as yet untapped natural products chemistry. In this review we touch on the historical context of microbial natural product discovery and discuss innovations and technological advances that are facilitating culture-dependent and culture-independent access to new chemistry from environmental microbiomes with the goal of re-invigorating the small molecule therapeutics discovery pipeline. We highlight the successful strategies that have emerged and some of the challenges that must be overcome to enable the development of high-throughput methods for natural product discovery from complex microbial communities.

Unique amalgamation of primary and secondary structural elements transform peptaibols into potent bioactive cell-penetrating peptides

“…2A). However, the addition of NaNO 3 to the PDB resulted in the suppression of polyketide biosynthesis and instead led to the production of at least 15 peptide natural products (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15), including the 22-mer peptaibol, gichigamin A (1), and six analogs [gichigamins B-G (2-7, respectively)] (Fig. 2B).…”

“…The effect was most highly pronounced when aromatic moieties (e.g., phenyl, biphenyl, naphthyl, coumarin, anthracene, and anthraquinone) (33)(34)(35)(36)(37)(38)(39) were introduced. In contrast, the coumarin-linked analog of alamethicin (43) exhibited only a minor increase in potency in PANC-1 cells (GI 50 6.75 μM for alamethicin and GI 50 structural features of the gichigamins were essential to the overall unique biological activity of this group of peptaibols. Intrigued by the dramatic increase in potency conferred by C-terminal modification of the gichigamins, we probed the biological effects of 22 versus 1.…”

“…Some of these techniques have been applied toward the creation of natural product big-data sets in which genomic, metagenomic, metabolomic, and proteomic approaches are combined to obtain new insights into nature's remarkable chemical bounty (4)(5)(6)(7)(8). The predictive capabilities of these methods have helped guide efforts in several fertile areas of natural products research including the DNA cross-linking enediynes (9), bioactive cyanobacterial metabolites (10,11), cytotoxic pentangular polyphenols (12), and thiopeptide antibiotics (13).…”

Reappraisal of actinomycetes for novel bioactive metabolites

“…These metagenomic approaches are normally either function or sequence based; the former screens and identifies cloned environmental DNA and evaluates the activity of their expression products, more specifically proteins as novel bioactive metabolites. The later concentrates on genes linked with production of specific natural products (Milshteyn et al, 2014).…”

A Collaborative European Approach to Accelerating Translational Marine Science

“…Lack of information to find suitable candidate bacteria with relevant activities for study and how to target them in the environment Contact MIRRI and EMBRC, who are making this knowledge available and have expertise in targeted isolation [20]; keeping pace with new developments, e.g., symposia, which infrastructure partners follow such as Natural Product Discovery and Development in the Genomic Era, organised by the Society for Industrial Microbiology and Biotechnology: https://sim.confex.com/sim/np2018/meetingapp.cgi Gaps in knowledge to be able to fully harness metagenomics, proteomics, and metabolomics to identify targets of interest with bioactive compounds or target gene clusters in bacteria with the desired properties Discovery can be enhanced by gene hunting and expression in host cells [19][20][21]; total DNA sequence data from samples can be matched with known genes and specific genes can be targeted [19]; predicting potential activities from the gene clusters is now possible [22]; reliable, verifiable, and efficient monitoring of biodiversity can be achieved via metabarcoding [23] A fundamental requirement of aquaculture breeding programs is the need to avoid inbreeding depression, which reduces the fecundity growth and robustness of stocks. Inbreeding control requires the development of genetic marker panels and software for pedigree reconstruction and parentage assignment ( Table 2).…”