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Scientists at TSRI and R.W. Johnson Pharmaceuticals Develop New Antibacterial Agents

La Jolla, CA. April 28, 1998 -- Scientists at The Scripps Research Institute (TSRI) and their colleagues at the R.W. Johnson Pharmaceutical Research Institute have developed a series of new antibacterial compounds designed specifically to target the biological mechanisms by which bacteria establish an infection in the host. With resistance to antibiotics an increasing public health threat, particularly in the hospital setting, the compounds offer the potential to provide protection against Staphylococcus aureus, or staph infection, vancomycin-resistant enterococci, and penicillin-resistant Staphylococcus pneumoniae.

According to the authors of the study, James A. Hoch, Ph.D., Professor, and John M. Whiteley, Associate Professor in the Department of Molecular and Experimental Medicine, "With infectious disease continuing to be our most serious health problem, this work represents important progress in a new target area for anti-infective therapy."

The study, "Antibacterial agents that inhibit two-component signal transduction systems," by J.F. Barrett, R.M. Goldschmidt, L.E. Lawrence, B. Foleno, R. Chen, J.P. Demers, S. Johnson, R. Kanojia, J. Fernandez, J. Bernstein, L. Licata, A. Donetz, S. Huang, D.J. Hlasta, M.J. Macielag, K. Ohemeng, R. Frechette, M.B. Frosco, D.H. Klaubert, J.M. Whiteley, L. Wang, and J.A. Hoch, appears in today's issue of Proceedings of the National Academy of Sciences, USA.

Due to the overuse of antibiotics and the failure of some patients to take a proper dosage of medication, resistance to antibiotics is becoming an increasing risk to public health. In May, 1997, the Centers for Disease Control and Prevention confirmed that Staphylococcus aureus had for the first time defended itself against vancomycin, the last drug reported to kill all of its strains. That strain, found in Japan, demonstrated an "intermediate" level of resistance to the antibiotic, a level higher than previously known for staph. It was the first time that the possibility of a strain of bacteria resistant to any antibiotic had appeared since penicillin became widely used in the 1940s.

In order for disease to result from bacterial infection, the expression of a series of genes must occur, allowing the prospective pathogen to adapt to the hostile environment in the host. Because this gene expression contributes to the virulence of the pathogens, the products encoded by the genes are referred to as "virulence factors." These factors contribute to the microorganism's ability to survive and grow at the site of the infection.

According to Hoch, "Impairment of one or more of these virulence factors by mutation, antibody neutralization or chemical inhibition can be the determining factor in tipping the outcome of the infection favorably toward the host. As a consequence, we are gaining an appreciation for the potential usefulness of bacterial virulence factors as new targets for therapeutic intervention against antimicrobial resistant pathogens. Two-component signal transduction systems are the only common regulatory elements shared by a wide range of virulence systems, raising the possibility that a broad spectrum inhibitor to such elements may suppress virulence in a variety of microorganisms."

This study shows the efficacy of the compound RWJ-49815 and its derivatives as the first series of inhibitors of two-component systems with demonstrated bactericidal activity against a broad range of microorganisms. The scientists are hopeful that these inhibitors targeting the signal transduction mechanisms will be useful new tools in the armamentarium against infectious disease. They speculate that human clinical trials could begin in two to three years.

Funding for the study was made possible by Johnson & Johnson and the National Institutes of Health.


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