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 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 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 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.