Mycobacterium tuberculosis is responsible for more human deaths than any other single infectious agent and imposes a considerable social and economic toll on a global scale. Adult pulmonary tuberculosis is notoriously difficult to control, requiring extended treatments with multiple antibiotics. Lack of compliance with these regimens has encouraged the appearance of multiple drug-resistant strains of M. tuberculosis. ? ? Effective control of tuberculosis requires better diagnostic methods, more efficacious vaccines, and better anti-mycobacterial drugs, particularly for treatments of latent and multi-drug resistant infections. Recent advances in mycobacterial genetics and the availability of several whole mycobacterial genome sequences brings considerable promise to the idea that elucidating the fundamental tenets of mycobacterial physiology, metabolism, genetics and structure will lead to novel strategies for controlling mycobacterial infections. Currently, we know little about the molecular basis of the fundamental aspects of such central questions as to why these bacteria grow so slowly, how is their unique cell wall synthesized, and how do mycobacterial cells communicate. Answering these central questions is important to understanding the molecular basis of mycobacterial pathogenesis and how we might intervene in it. ? ? Bacteriophages are powerful tools for understanding their bacterial hosts, and this is certainly true for the mycobacteriophages. Mycobacteriophages are partners in an extremely intimate relationship with their hosts; they are not only dependent on the host metabolic machinery for their replication and assembly, but they must also gain entry through a complex and hostile mycobacterial cell wall, and find ways to exit the cell once it is no longer of any use to them. Furthermore, mycobacteriophages may not kill their hosts at all but integrate their DNA into the host chromosome and co-exist peacefully. ? ? This project focuses on examining ways in which mycobacteriophages mimic the cellular signaling pathways of the mycobacteria. We have discovered that mycobacteriophage Bxbl integrates into the groEL1 gene, one of two groEL genes in the mycobacteria. Interruption of the groEL1 gene leads to the loss of biofilm maturation, apparently due to the inability to assemble the FAS-II enzyme complex for mycolate synthesis. We propose to elucidate the specific role of GroEL1 in biofilm formation and mycolic acid synthesis, and to determine its role in the pathogenesis of Mycobacterium tuberculosis. ? ? ?
