The Molecular Action of Actinorhodin, an Antibiotic Produced by Streptomyces coelicolor

Actinorhodin is a blue-pigmented, redox-active secondary metabolite that is produced by the bacterium Streptomyces coelicolor. Although actinorhodin has been used as a model compound for studying secondary metabolism, its biological activity is not well understood. Indeed, redox-active antibiotics in general have not been widely investigated at the mechanistic level. In this work, I have conducted a comprehensive chemical genetic investigation of actinorhodinâ s antibacterial effect on target organisms. I show that actinorhodin is a potent, bacteriostatic, pH-responsive antibiotic and that its redox activity, but not its in vitro organocatalyst activity, is important for its antibacterial activity. In the presence of actinorhodin, cells activate at least three stress responses, including those responsible for managing oxidative damage, protein damage, and selected forms of DNA damage. I find that mutations in the Staphylococcus aureus walRKHI operon can confer low level resistance to actinorhodin, indicating possible targeting of the cell envelope. This study indicates a complex mechanism of action for actinorhodin that is distinct from other redox-active compounds.