Grant: Operating Grant

The aim of this research is to determine how nickel use is regulated in bacteria. Nickel is an essential nutrient for many forms of life, including pathogenic bacteria such as Helicobacter pylori, which causes ulcers, gastritis and gastric cancers, and Escherichia coli, which can cause gastrointestinal illnesses. However, although these bacteria need nickel, they have to use it carefully because this metal can also be toxic if it is not handled carefully, so bacteria expend a lot of resources to control the distribution and accumulation of nickel. If these resources fail, the bacteria get sick and fail to grow. The focus of this grant is to understand how nickel use is regulated in several types of bacteria, and in the case of the H. pylori system, how the regulation of nickel is connected to the environmental niche of the organism: the human stomach. We will determine the chemical and biological details of the major proteins involved in these systems, and in doing so we will learn how we can disrupt their activities. This study will contribute to our knowledge of how heavy metals are used in biology, a fundamental aspect of life. Furthermore, the toxicity of transition metals, even essential nutrients like nickel, is a problem that must be dealt with by all organisms, and the nickel proteins serve as an excellent model system to study metal-dependent regulation. Finally, it is thought that humans do not have a dietary requirement for nickel, so the systems that control nickel in bacteria might provide unique targets for very 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 antibacterial agents an understanding of the details of these multi-faceted nickel systems is essential.