Grant: Project Grant

Emergence of antibiotic resistance among organisms responsible for infectious disease has outpaced new antibiotic development posing a serious health problem in Canada and globally. Significant efforts must be focused on developing new antibiotics if we are to avoid the return to a pre-antibiotic era of healthcare, when infection control did not exist - people at the mercy of microbes, the elderly dying from pneumonia, more children dying in infancy and treatments such as heart surgery or chemotherapy no longer possible. This proposal focuses on the assembly process of the bacterial ribosome. Ribosomes are essential enzymes for all bacteria, including major pathogens for humans. They are complex molecular nanomachines made up of over 50 components that synthesize all proteins in the cell. Their assembly pathway has tremendous potential but that has not been explored as a target for antimicrobials. We propose to determine the function of three essential proteins RbgA, YphC and YsxC, which precise molecular functions in the maturation of the ribosome remain to be elucidated. We will use an electron microscope to directly image these proteins to gain insights into how they work and how they interact with assembling ribosomal particles. Recent advances in electron microscope instrumentation provide an opportunity to see these structures at high resolution. Our work promises to give an unprecedented view of this essential bacterial enzyme. In addition, RbgA is widely distributed and homologs are found also in eukaryotes (including humans). Therefore, the proposed work will inform on ribosome assembly not only in bacteria but also in humans. Importantly, recent work has highlighted the importance of defective ribosome assembly in the development of blood cancers. Thus our work may also have relevance for development of cancer treatments.