Grant: Project Grant

Antibiotics are used to treat bacterial infections such as pneumonia, tuberculosis, sepsis and various kinds of infection that result from surgery or in patients whose immune system is compromised by chemotherapy. They are therefore at the front line of virtually all aspects of modern medicine. The efficacy of these incredible drugs, mostly discovered during the period from 1940-60, is being rapidly eroded through the antibiotic resistance. As a result, new antibiotics are desperately needed if we are to sustain our current standard of care. But the classical approaches to antibiotics discovery are not working all that well. The reason for this is that all of the available molecules in the world have been tested for the inhibition of growth of pathogens. New approaches are therefore desperately needed. We have discovered that the filamentous bacteria of the genus Streptomyces provide a fascinating alternative approach. Because these bacteria are filamentous in structure, they use many elements of the core molecular machinery (cell wall biosynthesis, cell division, chromosome segregation etc) differently than rod shaped or coccoid bacteria - which include almost all of the pathogens. Many processes which are essential for viability in pathogenic bacteria are employed primarily for sporulation in the streptomycetes. Our hypothesis therefore, is that screening for inhibitors of sporulation in Streptomyces has the potential to reveal novel inhibitors of these core processes and that these inhibitors might be developed as antibiotics against "conventional" bacteria. We have tested this hypothesis and thereby discovered three novel antibiotics: EN-7, Min-1 and Fil-1. In this project we will further develop these compounds in the hopes that we can provide valuable leads for fighting infectious disease.