The specific goal of this proposal is to initiate preclinical studies towards satisfying the requirements for an Investigative New Drug Application (IND) after identifying a compound(s) that could be commercialized and prescribed for the treatment of multidrug-resistant (MDR) Gram-positive hospital-acquired infections. The increased frequency of multidrug resistance in key pathogens has motivated us to employ our structure-based design approach to identify compounds that target multidrug-resistant (MDR) Gram-positive pathogens. For use in nosocomial infections caused by Gram-positive pathogens, a drug must cover Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Enterococcus faecium. Coverage of Streptococcus pneumonias (for treatment of patients who are either hospitalized due to community-acquired pneumonia or develop a Gram-positive pneumonia while hospitalized) and other species of staphylococci and enterococci would be highly desirable. To be commercially successful, it would be highly desirable for the drug to have pharmacokinetics commensurate with once or twice daily dosing. For life-threatening infections in the hospital, an IV agent would be needed, ideally followed by an oral formulation of the same drug. Looking ahead, this agent would cover strains that have resistance to macrolides, quinolones, vancomycin, ?-lactams, Synercid(r), and Linezolid. ? ? In our Phase I application, we set out to identify the active core of a new chemical entity that inhibits protein synthesis in the bacterial cell, determine its 3D structure when complexed to its target (the SOS subunit of the ribosome), and determine basic pharmacokinetics of one compound in this promising series. Having successfully completed all the goals from our Phase I application, we seek in this Phase II proposal to: ? ? 1. Determine MIC90 values for compounds with MICs = 5 ?g/ml against Gram-positive pathogens in our primary panel. ? 2. Determine efficacy in relevant animal models of infection. ? 3. Characterize compounds for potential to cause drug-drug interactions, adverse side-effects, microsomal lability, cytotoxicity, and for their potential to have oral absorption. ? 4. Characterize the pharmacokinetic profile of compounds in rodent and non-rodent species. ? 5. Determine how quickly resistance occurs with key compounds. ? 6. Initiate preclinical studies on a compound that meets acceptable criteria for treatment of nosocomial Gram-positive bacteria. ? ? It is expected that these units of work will provide substantial progress toward an IND filing of a compound active against Gram-positive nosocomial pathogens. ? ?
