Cryptic Chemical Communication: Secondary Metabolic Responses Revealed by Microbial Co‐culture

Abstract

Microbial secondary metabolites (SMs) have long been viewed as as ignificants ource of novel pharmaceutical and agrochemical molecules. With the increasing availability of genomic data, numerous biosynthetic gene clusters (BGCs) have been discovered. Despite the presence of tens of thousands of BGCs that can theoretically produce extremely diverse SMs, many gene clusters remain in as ilent state under axenic culture conditions. Co-culture is ap romising research approach as it stimulates the expression of cryptic BGCs to produce novel metabolites and also mimics naturali nterspeciesi nteractions in al aboratory environment. In recenty ears, the roles of SMs in microbial communication have caught the attention of researchers and our understanding of microbes and their productiono fr emarkable SMs has improved. SMs may be extensively involved in av ariety of communication eventsa mong microorganisms. We herein summarize certainr epresentative findings in the field of chemical communication involving SMs in co-culture systems.

A bioprocess perspective on the production of secondary metabolites by Streptomyces in submerged co-cultures

“…AA4 in the context of their competition for iron. A more detailed review concerning the mechanisms of metabolic responses in co-cultures was recently presented by Liu and Kakeya ( 2020 ).…”

“…Moreover, the co-cultivation approach may in some cases result in the enhanced levels of target products. Inducing and stimulating the production of secondary metabolites in microbial co-cultures is a topic that has been thoroughly reviewed (Arora et al 2020 ; Bertrand et al 2014 ; Chen et al 2020 ; Liu and Kakeya 2020 ; Zhuang and Zhang 2021 ), also in the context of the Streptomyces genus (Hoshino et al 2019 ; Kim et al 2021 ). However, the previous reviews were rather focused on the chemical spectrum of newly discovered or enhanced metabolites, not on the bioprocess-related aspects of co-cultivation.…”

An Atypical Arginine Dihydrolase Involved in the Biosynthesis of Cyclic Hexapeptide Longicatenamides

“…To date, more than 1,000 natural cyclic peptides have been reported, and the FDA/EMA approved more than 40 cyclic peptide drugs [1] . Co‐culture is considered to be a promising strategy to mining for novel bioactive cyclic peptides [2] . Very recently, we discovered two diastereomeric pairs of cyclic hexapeptides, longicatenamides A−D ( 1 – 4 , Figure 1A), which were isolated from the combined‐culture broth of Streptomyces sp.…”

“…[1] Co-culture is considered to be a promising strategy to mining for novel bioactive cyclic peptides. [2] Very recently, we discovered two diastereomeric pairs of cyclic hexapeptides, longicatenamides AÀ D (1-4, Figure 1A), which were isolated from the combinedculture broth of Streptomyces sp. KUSC_F05 with Tsukamurella pulmonis TP-B0596.…”

“…The measured values were roughly consistent with the theoretical stoichiometric relationships expressed as Eqs. (1) and (2).…”