Resistance-guided antibiotic discovery

Environmental microbes are outstanding sources of antibiotics. Expanding the activity of these antibiotics, for example towards a broader group of pathogens or resistant organisms, can often be achieved by modification of the core chemical scaffold. Increasing antibiotic chemical diversity can be achieved using synthetic biology approaches for example by harnessing the biosynthetic capacity of various accessorizing enzymes that often are found in antibiotic producing organisms. Indeed it is the actions of these enzymes that are the sources of much of the chemical diversity of various antibiotic classes produced by environmental organisms. However selectively identifying individual strains that produce members of a given antibiotic class can be very challenging and time consuming. We have developed a method that combines the use of antibiotic self-resistance in producing bacteria to enrich the pool of antibiotic producers by orders of magnitude. Combining this strategy with phylogenetic analysis of selected biosynthetic genes enables rapid identification of producers of known and novel members of antibiotic classes. These can be sources of new compounds and new enzymes that can have roles in downstream synthetic biology platforms to increase antibiotic chemical diversity.