Do Global Regulators Hold the Key to Production of Bacterial Secondary Metabolites?

Abstract

The emergence of multiple antibiotic resistant bacteria has pushed the available pool of antibiotics to the brink. Bacterial secondary metabolites have long been a valuable resource in the development of antibiotics, and the genus Burkholderia has recently emerged as a source of novel compounds with antibacterial, antifungal, and anti-cancer activities. Genome mining has contributed to the identification of biosynthetic gene clusters, which encode enzymes that are responsible for synthesis of such secondary metabolites. Unfortunately, these large gene clusters generally remain silent or cryptic under normal laboratory settings, which creates a hurdle in identification and isolation of these compounds. Various strategies, such as changes in growth conditions and antibiotic stress, have been applied to elicit the expression of these cryptic gene clusters. Although a number of compounds have been isolated from different Burkholderia species, the mechanisms by which the corresponding gene clusters are regulated remain poorly understood. This review summarizes the activity of well characterized secondary metabolites from Burkholderia species and the role of local regulators in their synthesis, and it highlights recent evidence for the role of global regulators in controlling production of secondary metabolites. We suggest that targeting global regulators holds great promise for the awakening of cryptic gene clusters and for developing better strategies for discovery of novel antibiotics.

Whole‐Cell MALDI‐ToF MS Coupled with Untargeted Metabolomics Facilitates Investigations of Microbial Chemical Interactions

“…Secondary metabolite production is well characterized in B. thailandensis E264 [9a,e,16] . The majority of BGCs in this bacterium remain silent under most culture conditions [9,17] .…”

Extracytoplasmic Function Sigma Factors Governing Production of the Primary Siderophores in Pathogenic Burkholderia Species

“…Some are produced by the modular non-ribosomal peptide synthetases (NRPS), whereas others are the product of NRPS-independent siderophore synthases ( Crosa and Walsh, 2002 ; Carroll and Moore, 2018 ). Biosynthetic gene clusters encoding proteins responsible for production and transport of secondary metabolites such as siderophores are often large, and the genes are subject to tight regulation ( Thapa and Grove, 2019 ). Such regulation may involve global transcriptional regulators, which generally regulate a large number of genes with distinct functionalities, and/or it may depend on local cluster-specific regulators, which are dedicated to a certain pathway.…”

AHL-Based Quorum Sensing Regulates the Biosynthesis of a Variety of Bioactive Molecules in Bacteria

“… The QS system, composed of BtaI2 and BtaR2, controls bactobolin production , and their encoding genes ( btaI2–btaR2 ) are located in the bactobolin operon (Figure ). Bactobolin was identified because of its antimicrobial activity against a broad range of bacteria including Bacillus subtilis , , Bacillus cereus , Chromobacterium violaceum , Staphylococcus aureus , and Escherichia coli and antifungal activity against Candida krusei. Bactobolin inhibits protein synthesis by binding to the 50S ribosomal subunit in proximity to the L2 protein. ,− Besides its antimicrobial effects, 1 was reported to have antitumor activity in vitro on different cell types , and in vivo in murine models. , A recent study demonstrated that the disruption of QS considerably altered the proteome of B. thailandensis E264, including the biosynthesis of bactobolin molecules, as well as various secondary metabolites such as 4-hydroxy-3-methyl-2-alkenylquinoline (HMAQ; 2 ) and its derivatives, whose production was considerably impacted …”