Generation of novel drugs against drug resistant bacteria through engineering of

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DESCRIPTION (provided by applicant): The number of patients treated for antibiotics-resistant bacterial infections has increased drastically in recent years. What started as a problem primarily associated with hospital-acquired Enterococcus infections, has not only moved into the general community, but also grown to include a number of widespread and serious pathogens. Drug-resistant Streptococci, Staphylococci, Enterococci and Pseudomonas strains are quite common. Currently as many as 70% of hospital-acquired infections in the US are resistant to at least one antibiotic, and about 40% of S. aureus infections are multidrug-resistant. Even drugs like Vancomycin and Teicoplanin, which for years represented the "agents of last resort" for treatment of antibiotics-resistant infections, are no longer efficacious against certain pathogen strains. The loss of efficacy of these compounds leaves very few treatment options for patients with multi-drug resistant infections. Clearly, there is an immediate unmet need for new antibiotics with novel modes of action. Moreover, the overall market for antibacterial drugs is large and growing - world-wide sales reached $30 billion in 2006. Early published data suggest that empedopeptin, a cyclic peptide produced by Empedobacter haloabium, has considerable potency towards a wide range of Gram positive organisms, in vitro. This data also suggest that the compound is well tolerated in mice and quite efficacious against systemic infections of Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae. Nonetheless, although discovered over 20 years ago, empedopeptin has not been developed into a commercial product. A recent, in vitro evaluation of empedopeptin has revealed that the compound also has significant potency against most contemporary, drug-resistant, Gram-positive organisms, including meticillin-resistant S. aureus (MRSA), meticillin-resistant S. epidermis (MRSE) and vancomycin-resistant Enterococci (VRE). Together with the published animal data, this suggests that empedopeptin may have the properties required for development into a drug for the treatment of infections caused by today's antibiotics-resistant organisms. However, a lack of patent protection together and somewhat high MIC values towards several pathogens currently constitutes a barrier to development of the compound. The overall goal of the project outlined in this proposal is to use of a genetic engineering approach to generate novel derivatives of the antibacterial compound empedopeptin. This will allow improvement of the compound's therapeutic properties, as well as creation of an intellectual property situation that is compatible with commercial development of the compound as a drug for the treatment of antibiotics-resistant bacterial infections. However, an absolute prerequisite for any genetic engineering-mediated structural modifications of empedopeptin is availability of the corresponding (currently unknown) biosynthesis gene. Consequently, the goal of Phase I is to identify, isolate and characterize this gene. PUBLIC HEALTH RELEVANCE: The drastic increase in multi-drug resistant infections, during last two decades, has generated an immediate unmet need for new antibacterial drugs with novel modes of action. The proposed project will add a potent, efficacious, well-tolerated and economical antibacterial drug to a currently quite limited inventory of compounds with efficacy towards a broad range of clinically relevant drug- and multi-drug resistant Gram-positive pathogens.