Understanding and exploiting general transcription factors in the antibiotic-producing Streptomyces

点击翻译按钮获取中文摘要

Most of our antibiotics derive from the Actinobacteria, a phylum of Gram positive bacteria that inhabit diverse terrestrial and aquatic habitats and includes the Streptomyces genus that produce, for example, chloramphenicol, neomycin and erythromycin. While the use of antibiotics in the second half of the 20th century transformed human health care, antimicrobial resistance in pathogenic bacteria has steadily increased and now presents itself as a major global threat to health and society. Researchers are therefore hunting for new antibiotics to replace those that are becoming obsolete and the Actinobacteria are being revisited as a major source. One reason is because recent analysis of genome sequences is revealing genes that might direct antibiotic production, but are not switched on under laboratory conditions. Scientists are therefore very interested in finding new ways to switch on such cryptic biosynthetic genes so that the products can be assayed. One approach is to generate mutations that affect the structure and function of RNA polymerase - the enzyme that transcribes (reads) DNA to generate an RNA copy that can then be translated into the respective protein. Certain mutations are thought to redistribute the RNA polymerase away genes involved in growth towards those involved in secondary metabolism including antibiotic production. These mutations might mimic the behavior of this enzyme when the bacteria run out of nutrients - the so called stringent response that ensures that RNA polymerase switches from transcribing genes involved in growth to those involved in surviving the stress. However, this process is poorly understood in Actinobacteria and recent findings have shown that RNA polymerase itself differs from well-studied model organism E. coli in containing two accessory protein factors, called RbpA and CarD, that are required for transcription. This project will investigate the stringent response and its relationship with these transcription factors. It will produce new knowledge that will help us understand the role of RbpA and CarD and generate new new ways to reactivate cryptic antibiotic biosynthetic gene clusters and engineer, using synthetic biology, new recombinant bacterial strains for the production of novel antimicrobials.