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

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.

Global Awakening of Cryptic Biosynthetic Gene Clusters in Burkholderia thailandensis.

Many bacteria encode biosynthetic proteins that produce a vast array of natural products. These compounds are often synthesized during host invasion as they function as virulence factors. In addition, such secondary metabolites have yielded numerous molecular scaffolds with pharmaceutical and clinical importance. The gene clusters that encode proteins responsible for synthesis of these compounds are typically silenced or "cryptic" under laboratory growth conditions, hampering discovery of novel lead compounds. We report here that MftR is a global repressor of secondary metabolite synthesis in Burkholderia thailandensis and that urate functions as a physiologically relevant inducer of gene expression. Biosynthetic gene clusters under MftR control include those associated with production of the antimicrobial bactobolins, the iron siderophore malleobactin, and the virulence factor malleilactone. MftR also controls additional genes associated with survival in a host environment, such as genes encoding components of the type III secretion system (T3SS) and proteins linked to anaerobic respiration. This observation not only has implications for understanding activation of gene regulatory networks during host invasion, but it also paves the way for isolation of novel therapeutic leads.