“Let’s cultivate science for its own sake without continuously considering its applications. They will always come, maybe in years or perhaps in centuries. The course of progress would have suffered if Galvani, Volta, Faraday and Hertz, who discovered the principles of electricity, have discarded their findings because there were no applications for them at the time”. Ramon y Cajal.
New Antimicrobial Targets
Emergence of antibiotic resistance among organisms responsible for infectious disease has outpaced new antibiotic development posing a serious health problem in Canada and globally. With the alarming increase in antibiotic resistance to many common bacterial pathogens, infectious diseases rank as the third-leading cause of death in Canada. New approaches and significant efforts must be focused on developing new antibiotics if we are to avoid the return to a pre-antibiotic era of healthcare. In our laboratory we aim to obtain a comprehensive understanding of the structure and function of new antimicrobial targets, developing them into tangible enzymes for intervention with new antibiotics. Current work focuses on the assembly process of the ribosome; a pathway of tremendous potential but that has not been explored as a target for antimicrobials yet. Our recent work shows that the molecular structure of ribosome assembly intermediates provides an effective platform to develop new antibiotics against this fundamental cellular process.
Understanding how Ribosomes Assemble
Ribosomes are responsible for the process of decoding mRNA into proteins, a process essential to sustain life. Bacteria with defects in ribosome biogenesis exhibit slower growth and severely reduced ability to cause disease. Ribosomes are arguably the most complex molecular nanomachines in the cell. They are comprised of a small (30S) and a large (50S) subunit and overall they contain over 50 different components. In recent years, extraordinary efforts in structural biology have provided atomic structures of the ribosome generating a detailed three-dimensional view of the process of protein synthesis and how antibiotics currently used in the clinic function by targeting the mature ribosome. These structures have been essential to both find new antibiotics as well as to make existing ones more powerful. However, atomic resolution structures of ribosome assembly intermediates have not been obtained and the present structural understanding of the intricate process of assembly of the ribosome is very superficial. This void of knowledge limits our ability to develop new antibiotics targeting the process of ribosome assembly. Our laboratory uses cryo-EM to obtain atomic resolution structures of ribosome assembly intermediates and visualize in 3D the complexity of this process. Structural biology techniques have been instrumental in the discovery of antibiotics targeting the mature ribosome. The atomic resolution structures of immature ribosomes obtained in our laboratory are having the same impact and are providing an extensive reservoir for the discovery of new antibiotics that target ribosome assembly.