Small‐molecule elicitation of microbial secondary metabolites

Abstract

SummaryMicrobial natural products continue to be an unparalleled resource for pharmaceutical lead discovery, but the rediscovery rate is high. Bacterial and fungal sequencing studies indicate that the biosynthetic potential of many strains is much greater than that observed by fermentation. Prodding the expression of such silent (cryptic) pathways will allow us to maximize the chemical diversity available from microorganisms. Cryptic metabolic pathways can be accessed in the laboratory using molecular or cultivation‐based approaches. A targeted approach related to cultivation‐based methods is the application of small‐molecule elicitors to specifically affect transcription of secondary metabolite gene clusters. With the isolation of the novel secondary metabolites lunalides A and B, oxylipins, cladochromes F and G, nygerone A, chaetoglobosin‐542, ‐540 and ‐510, sphaerolone, dihydrosphaerolone, mutolide and pestalone, and the enhanced production of known secondary metabolites like penicillin and bacitracin, chemical elicitation is proving to be an effective way to augment natural product libraries.

Fungal Endosymbionts of Seaweeds

“…Pestalotia sp., another marine-derived fungus, synthesizes pesatlone, an antibiotic effective against methicillin-resistant Staphylococcus aureus when cultured with a marine bacterium (Cueto et al 2001). The synthetic ability of the fungi can also be enhanced by the presence of small molecule elicitors in the growth medium as they specifically effect the transcription of secondary metabolite gene clusters (Pettit 2010). For instance, Christian et al (2005) reported that the marine-derived fungus Phomopsis asperagi produces novel chaetoglobosins when the growth medium is amended with the sponge metabolite jasplakinolide.…”

“…For instance, Christian et al (2005) reported that the marine-derived fungus Phomopsis asperagi produces novel chaetoglobosins when the growth medium is amended with the sponge metabolite jasplakinolide. The addition of small molecule elicitors to the fermentation medium specifically influences the synthesis of bioactive molecules by fungi (Pettit 2010). Thus, the synthetic ability of seaweed endosymbionts can be enhanced by altering the culture conditions.…”

One-step high-efficiency CRISPR/Cas9-mediated genome editing in <italic>Streptomyces</italic>

“…More than two-thirds of natural antibiotics [11,12] and large numbers of intermediates for semi-synthetic drug development [13][14][15] originate from Streptomyces. Whole genome sequencing of Streptomyces has uncovered a large group of cryptic secondary metabolite biosynthetic gene clusters, most of which are structurally and functionally unknown and represent an important asset for the discovery of pharmaceutically valuable compounds [16][17][18][19][20].…”

Addition of Zinc, Manganese, and Iron to Growth Media Triggers Antibiotic Production in Bacterial Isolates From the Lower Atmosphere

“…Ochi and Hosaka (2013) indicated that rare earth metals and trace metals, notably manganese, zinc and iron may trigger the production of various secondary metabolic pathways. Actinobacteria have complex metabolic interactions with metals (Abbas & Edwards, 1989;Abbas & Edwards, 1990;Haferberg & Kothe, 2007;Paul & Banerjee 1983;Pettit, 2011). For instance, Yamasaki, Furuya, & Matsuyama (1998) showed that the impact of a metal ion on an isolate's antibiotic production varies depending on the anionic species to which it is associated.…”