Regulatory networks and ecological cues that control antibiotic production by actinomycetes

Actinomycetes are prolific producers of natural products, including anticancer compounds, antifungals and antibiotics. The treasures that lie hidden in the actinomycete genomes may well be our final resource in the battle against the rapidly emerging infectious diseases associated with multi-drug resistance. We aim to understand the triggers and cues that elicit antibiotic production in the soil as well as in the laboratory. For this we use a combination of ecological insights, systems biology and genome mining to uncover the regulatory mechanisms that control antibiotic production. We then apply this for the discovery of novel antimicrobials. One major control system revolves around the nutrient sensory protein DasR, which pleiotropically controls antibiotic production. Many other control systems are undoubtedly in place to allow actinomycetes to respond appropriately to challenges by competitors and fluctuations in nutrient composition in the habitat. Furthermore, once a bioactivity is elicited under specific growth conditions, novel approaches are needed to rapidly identify the bioactivity of interest and link it to a specific gene cluster. Molecular and ecological insights to elicit antibiotic production will be discussed, and examples of antibiotics identified by these approaches presented.