Grant: Operating Grant

Modern medicine is dependent on effective antibiotic drugs. Unfortunately, antibiotic resistance is spreading rapidly causing a steady erosion of treatment for hospital- and community-acquired infections. The need for new antibiotics is therefore a central challenge. Ironically, most large pharmaceutical companies have abandoned antimicrobial research. Most antibiotics are produced by streptomycetes bacteria. These organisms are easy to work with but fail to produce most of the antibiotics encoded in their genomes during laboratory growth. Our goal is to overcome this 'expression barrier' so that we can identify and take advantage of these cryptic antibiotics. As a result of our collaboration we have discovered an innovative way to genetically modify streptomycetes so that they express their antibiotic biosynthetic genes. Using this technology we have identified two potent new compounds. Our approach works in all of the strains we have tested and the antibiotic lead compounds we have discovered kill many antibiotic resistant superbugs. Importantly, the activity of these antibiotics is restricted to bacteria, suggesting that they will have minimal adverse effects in humans. This is a vital property for possible clinical use. The work we are proposing will deliver two things. First, we will create a universally applicable and commercializable version of our antibiotic triggering technology, based on the prototypes we have used so far. Second, we will characterize the mode and range of action of the antibiotics we have discovered and produce them at sufficiently large scale for pre-clinical research and clinical trials.