Grant: Operating Grant

The aim of this research is to determine how bacteria make a nickel-containing protein called hydrogenase. This protein is essential in many microorganisms, including pathogens such as Escherichia coli, which causes gastrointestinal illnesses, and Helicobacter pylori, which causes ulcers, gastritis and gastric cancers. Hydrogenases are vital because they allow bacteria to use hydrogen gas as energy, and if the hydrogenase protein is not correctly produced the bacteria get sick and fail to grow. For hydrogenase to function it requires a nickel ion, and this metal is specifically imported into the bacteria cell and delivered to the hydrogenase protein through the coordinated activity of helper proteins. The purpose of this grant is to understand how bacteria produce hydrogenase, with a focus on nickel acquisition and delivery. We will define the key steps of this fascinating system, revealing the mechanisms of the underlying processes. We will also identify molecules that block hydrogenase production; such compounds can be used as investigative tools and may serve as lead compounds in the design of new antimicrobial therapies. This study will contribute to our knowledge of how nickel is used in biology, a fundamental aspect of life. Furthermore, the production of proteins with complex metal centers occurs throughout Nature, and the hydrogenase biosynthetic proteins serve as an excellent model system to understand these types of processes. Finally, humans do not require nickel, so the systems that make the nickel-containing hydrogenases will provide unique targets for selective antibiotics. Despite the huge advances in antibiotic development, bacterial infections remain a serious health problem, and new types of treatment are needed. In order to realize the potential of a new strategy for antimicrobial agents a detailed understanding of these multi-faceted nickel systems is essential.