Grant: Project Grant

Antimicrobial resistance is on track to become the next global pandemic. A recent analysis of this emerging threat predicts grim scenarios and alarming economic estimates that are not difficult to imagine while still immersed in the Covid-19 pandemic. In the last three decades, discovery efforts have been limited to generate improved versions of legacy antibiotics that target conventional vital pathways in bacterial species causing infectious diseases. Resistance to these modified drugs quickly emerges. Developing novel antibiotics that target unexplored cellular processes not susceptible to existing resistance mechanisms is urgent. This proposal focuses on the assembly process of the bacterial ribosome, which is not currently targeted by any antibiotic. Ribosomes synthesize all cellular proteins. If an organism cannot make ribosomes, it dies. Ribosomes are complex molecular nanomachines made up of over 50 components. We found that critical steps within the ribosome assembly process have tremendous potential as targets for developing novel antibiotics. Our recent work identified one of these critical steps. Three proteins, RbgA, YphC and YsxC, bind to the assembly intermediate that accumulates at this step. The three proteins are essential for the 50S subunit to reach its mature state. In this proposal, we seek to answer how exactly RbgA, YphC and YsxC act to complete the maturation of this critical assembly intermediate and transform it into a functional 50S subunit. We will use an electron microscope to directly image these proteins to gain insights into how they interact with the assembling subunit and the maturation steps they catalyze. Uncovering these critical steps in the assembly process will allow leveraging ribosome biogenesis factors as a novel antimicrobial target and discovering new antibiotics that will help curve the rapidly emerging threat of antimicrobial resistance.