Combinatorial biosynthesis of antibiotics: challenges and opportunities

Natural products with antibiotic activity have been central agents in human therapeutics over the past fifty years. They are likely to remain crucial in the decades to come. These molecules, often termed secondary metabolites because they are the end products of dedicated metabolic pathways that are turned on when microbes are stressed by environmental factors such as starvation, can achieve considerable architectural and functional group complexity that allows specific targeting. The programmed manipulation of the genes that encode the enzymes in the biosynthetic pathways offers promise for redesign of antibiotic structures to create new activities and overcome bacterial resistance to existing antibiotics.