The hidden enzymology of bacterial natural product biosynthesis

Abstract

Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic enzymes that construct core scaffolds or perform peripheral modifications, and can thus define natural product families, introduce pharmacophores and permit metabolic diversification. Modern genomics approaches have greatly enhanced our ability to access and characterize natural product pathways via sequence-similaritybased bioinformatics discovery strategies. However, many biosynthetic enzymes catalyse exceptional, unprecedented transformations that continue to defy functional prediction and remain hidden from us in bacterial (meta)genomic sequence data. In this Review, we highlight exciting examples of unusual enzymology that have been uncovered recently in the context of natural product biosynthesis. These suggest that much of the natural product diversity, including entire substance classes, awaits discovery. New approaches to lift the veil on the cryptic chemistries of the natural product universe are also discussed. Bacterial natural products (NPs) are specialized metabolites that encompass an extraordinary breadth of different biological activities, many of which are of considerable value to society. NPs or NP-inspired compounds represent ~65% of all small-molecule approved drugs 1 used in medicine to treat infectious diseases, cancers or as immunosuppressants 2 , and they are also applied extensively in agriculture 3. While NPs have been an extremely productive source of new leads for the chemicals that are integral to modern life, rapid increases in resistance to antibiotics, cancer chemotherapies and pesticides pose significant threats to medicine and agriculture 4,5 .

Diversity and Distribution of Volatile Secondary Metabolites Throughout Bacillus subtilis Isolates

“…Isotopic labeling of certain appropriate nutrient compounds may also help to pin down volatile secondary metabolites to specific biosynthetic pathways. The biosynthesis of several microbial secondary metabolites and possible precursor substrates were already excellently described for other bacterial species (Schulz and Dickschat, 2007;Korpi et al, 2009;Scott and Piel, 2019). Nevertheless, the gap in knowledge about the biosynthesis of many volatiles in B. subtilis could be filled by using isotopic labeling of substrates.…”

Volatilomes of Bacterial Infections in Humans

“…So far (only) six out of 26 known bacterial phyla have been investigated regarding their volatile emission, corresponding to a very small proportion of known species (i.e., 0.00000006%) that is presently found in the database (Lemfack et al, 2020). It can be envisioned that the large number of diverse microbial genomes yet to be analyzed harbor hidden metabolic and physiological potentials, which could produce a large number of compounds during both primary and secondary metabolism, and under various nutritional conditions (Donia and Fischbach, 2015;Piechulla et al, 2017Piechulla et al, , 2020Scott and Piel, 2019;Lemfack et al, 2020). These exceptional microbial features have become increasingly important with the realization that humans have to be considered as holobionts, as they contain communities of microorganisms within their bodies as well as on their skin (Grice et al, 2009;Grice and Segre, 2011;Marchesi, 2011;Bouslimani et al, 2015; Figure 1).…”

Plant Endophytes and Epiphytes: Burgeoning Sources of Known and “Unknown” Cytotoxic and Antibiotic Agents?

“…The following examples do not formally address endophytes and epiphytes but are indicative of the methods that can be used to help define the methodologies for successful pro-duction of cytotoxic (and other agents) from microbes/hosts. These include, but are not limited to, eliciting secondary metabolism in actinomycetes [114][115][116][117], methodologies for identifying the compounds produced [118][119][120][121][122], where they are localized [123], analyses of fungal BGCs to published natural product structures [124,125], small-scale plate-based techniques for fungal coculture [126,127], on-demand production of secondary metabolites [128], mixed culture of endophytes [129], metabolomics in induced cultures [130][131][132][133][134][135], use of synthetic biological techniques to further expand the chemical biodiversity discovered [132], a 2016 review on a number of approaches used to study the expression of cryptic BGCs by Zarins-Tutt et al [136], and a more recent follow-up by Scott and Piel [137].…”