It is proposed to evaluate two different non-antibiotic strategies for the treatment of infections caused by MRSA and other staphylococci. The first of these involves the inhibition of virulence through blocking of the expression of the major global virulence regulatory determinant, agr. This can be accomplished by means of homologs of the agr autoinducing peptides, AIPs. These peptides bind to AgrC, the agr receptor, and inhibit transmission of the agr-activating signal. We have identified a peptide that is a universal inhibitor agr expression for S. aureus and propose to investigate derivatives of this peptide that are intended to improve stability, serum retention, and inhibitory activity. Further study of these peptides and the synthesis of new variants will be undertaken in collaboration with Dr. Tom Muir or Rockefeller University. The second strategy involves lysostaphin, a potent staphylolytic enzyme that has been shown to have powerful therapeutic effectiveness in animal models indeed, it is the only agent that will sterilize cardiac vegetations in experimental endocarditis. Additional pre-clinical trials are proposed to determine its effectiveness against refractory infections such as osteomyelitis, septic arthritis, and foreign body infections, with or without biofilm formation. Lysostaphin is nearing readiness for clinical trails and it is proposed to complete its development as a commercial product. This part of the program will be undertaken by Bharat Biotech, Ltd, which holds the patent on a novel method of production and purification of the enzyme.
As antibiotics are becoming less and less effective against bacteria such as the notorious MRSA, there is a great need for new anti-infective strategies that do not involve conventional antibiotics. We propose to develop and implement two such strategies, one involving peptides that block the production of toxins and other injurious bacterial proteins, the other making use of a powerful enzyme that dissolves MRSA and other staphylococci within the body, thus rapidly curing an infection.
