Studies of the Staphylococcus aureus cid and lrg operons have provided importantinsight into the regulatory control of bacterial murein hydrolase activity and autolysis and haveled to a model in which this system is functionally analogous to the control elements ofprogrammed cell death (PCD) in more complex eukaryotic organisms. Although the Cid and Lrgproteins have been shown to be similar to bacteriophage holins and antiholins, respectively,which are fundamental to the control of cell death and lysis during the lytic stage of abacteriophage infection, the precise molecular/biochemical mechanisms utilized by theirbacterial counterparts during cell death and lysis remain to be determined. In the currentproposal, we have built on recent studies in our laboratory demonstrating that cytoplasmicacidification and pyruvate metabolism are critical aspects of bacterial cell death to probe thespecific functions of the Cid and Lrg proteins. In the first specific aim we will utilize a moleculargenetic approach to examine the relationship between the CidA/B proteins and pyruvatemetabolic enzymes in the control of bacterial cell death. The second aim will utilize a biophysicalapproach to test the model that Cid- and Lrg-mediated transport is a fundamental aspect of thecontrol of bacterial cell death. The third and final aim will explore the CidR-mediated regulationof this system with a focus on the identification of the effector molecule(s) that induces itsactivity. Overall, the results generated by the experiments described in these aims will illuminatethe molecular mechanisms underlying bacterial PCD and uncover the metabolic controlelements required for its regulation, ultimately leading to improved therapeutic strategies to fightbacterial infections.
|Effective start/end date||5/24/16 → 4/30/21|
- National Institutes of Health: $376,250.00