Raul Barletta, PhD

Dr. Raul G. Barletta is a microbiologist with over 25 years of experience with pathogenic microorganisms. His particular areas of interest are in diseases that are of chronic nature and difficult to diagnose: Tuberculosis (TB), Bovine Tuberculosis and Johne's disease (JD). There are no effective vaccines against these devastating diseases caused by mycobacterial pathogens. In addition, antibiotic resistance, especially in TB, has made it difficult to prevent and treat these conditions. Dr. Barletta hopes his research will lead to vaccines, new drugs and research tools to provide more accurate and faster tests to identify these pathogens. His approaches are based on the understanding of mycobacterial physiology by the use of molecular genetics and redox biology. His laboratory actively collaborates with the Department of Chemistry in Nuclear Magnetic Resonance metabolomics (Dr. Robert Powers) and chemical synthesis (Drs. Patrick H. Dussault and James M. Takacs). He also works on the development of novel diagnosis that could be adapted to all mycobacterial diseases, whether they inflict humans or animals.

Research Description:

Re-emergence of TB is caused by multiple drug-resistant strains and the need to develop new drug therapies and other control strategies. In this aspect, my research on anti-TB drug development and biodefense focuses on D-alanine racemase and D-alanine ligase, the presumed lethal target of D-cycloserine, an analog of D-alanine. This enzyme forms the critical dipeptide D-alanyl-D-alanine, an essential building block of peptidoglycan. Institutional grants allowed my laboratory to develop a "proof of concept" in the model system Mycobacterium smegmatis while a National Institutes of Health grant permitted us to further pursue the development of D-alanine ligase as a target for rational drug design. My laboratory analyzed the crystal structure of this drug target by completing collaborations with Dr. James Sacchettini (Department of Biochemistry and Biophysics, Texas A&M University). These research studies resulted in various publications and the granting of a US patent. 
 

Ongoing Research:

1. Determine the essential roles of D-alanine ligase and D-alanine racemase in the physiology of Mycobacterium tuberculosis (MTB).
    
2. Search for novel inhibitors of the MTB D-alanine ligase that could serve as novel anti-tuberculosis drugs.
    
3. Expand drug target search to additional essential steps in peptidoglycan biosynthesis and D-alanine metabolism such as L-alanine dehydrogenase.
    
4. Determine the mechanisms of redox homeostasis underlying tuberculosis latency.
    

Other Research Interest:

JD, caused by Mycobacterium paratuberculosis (MAP), affects up to 34% of US dairy and beef cattle herds and can cause economic losses of up to $1.5 billion per year. This slow-growing organism doubles the generation time of MTB. My laboratory was the first to develop a gene transfer system for MAP. Since then, we have demonstrated the expression of reporter genes and their usefulness to track the microorganism and test drug susceptibility. I contributed to the University of Minnesota's DNA sequencing project, by identifying the prototype strain to be sequenced, a proposal that was based on our prior observations regarding the feasibility of genetic manipulations for this strain. We have recently generated a complete MAP mutant bank and identified mutants that are attenuated in bovine macrophages. These mutants are now being tested in animal models by the interdisciplinary multi-state vaccine testing program sponsored by the Johne's Disease Integrated Program and United States Department of Agriculture Animal and Plant Health Inspection Service.

Teaching and Training Program:

My teaching commitments involve pathogenic microbiology courses: I am the main instructor of Basic (VBMS424/824) and Advanced (VBMS951) Infectious Diseases, and contribute to lectures in Pathogenic Microbiology (VBMS441/841) and VMED666. These courses are an essential component to instruct both undergraduate and graduate students interested in the molecular basis of infectious diseases. The Advanced course is also geared to provide elements of proposal writing to advanced graduate students. Regarding training, 3 senior personnel, 3 post-doctoral fellows, and 13 graduate students (3 PhD and 10 MS) trained under my supervision.