Understanding how metal ions traverse the bacterial cell membrane
Bacterial infections are highly dependent on metal ion micronutrients. The high affinity uptake pathways are encoded for by ABC permeases that acquire metal ions from the extracellular environment. Of particular interest to our group are the metal ions manganese and zinc. Manganese has important roles during infection and colonization, where it serves in carbon metabolism and oxidative stress response, whereas zinc is an essential cofactor for numerous cellular functions. The manganese and zinc ABC importers have been shown to be essential for the virulence of a number of human pathogens.
1. Manganese uptake in Streptococcus pneumoniae and other pathogens
Bacterial pathogens must scavenge their metal ions from the host environment in order to mediate virulence. Streptococcus pneumoniae is the world's foremost bacterial pathogen and is responsible for more than one million deaths every year. In terms of relative disease burden, it is the largest bacterial killer of young children and kills more children every year than AIDs, tuberculosis and malaria combined. However, its ability to infect and cause disease is dependent on the acquistion of metal ions. Manganese is an important metal ion for this pathogen and loss of manganese uptake completely prevents its ability to cause disease.
Our group seeks to understand how S. pneumoniae, and other pathogens, scavenge manganese from the host environment. Although it was known an ABC importer was involved in this process, the underlying details were pooly understood. Recently we revealed the mechanism by which S. pneumoniae scavenges manganese from the host environment and how another metal ion, zinc, interfered with this process. We found that the manganese recruiting protein, PsaA, used a 'spring-hammer' mechanism to bind metal ions, in which half of the protein pivoted and closed over the other half.
There are still many unanswered questions that we are currently investigating. These include how this importer is selective for manganese ions, how are manganese ions are translocated into the bacterial cell, and can the host prevent manganese from being scavenged by bacteria during infection. Answering these questions will provide the necessary information to design the next generation of antimicrobial agents to target this essential bacterial pathway.
2. Zinc homeostasis in Streptococcus pneumoniae
Zinc is the second most abundant transition row element in biological systems. This metal ion has crucial roles in numerous cellular processes such as transcription, translation, catalysis and metabolism. As with all nutrients, pathogenic bacteria must scavenge zinc from the host in order to mediate disease.
Our studies have shown that manganese and zinc have an unusual relationship in S. pneumoniae, where zinc can actually block the manganese ABC importer. So we are seeking to understand how zinc is acquired and managed in this organism. Recently work from our lab identified that zinc uptake in S. pneumoniae, although similar to manganese uptake, was regulated in a more complex manner. Intriguingly zinc was recruited by 2 proteins, AdcA and AdcAII. A number of possible models have been proposed for how these proteins work together to recruit zinc.
Work in our group is focused on understanding how zinc is sensed by S. pneumoniae, how is zinc managed once it has been translocated into the cell, and how does the host utilise zinc during infection. The answers we obtain to these questions will lead to new ways to target this major human pathogen and its need for zinc.