The long-term goal of this project is to develop a novel therapy to combat a growing human healthcare problem arising from the emergence of bacteria that are resistant to vancomycin. Vancomycin is the last resort for many of the 1.5 million hospital- and nursing home-acquired infections every year leading to 80,000 deaths caused by bacteria that are already resistant to commonly used antibiotics. Novel catalytic antibodies will be created to target the molecular basis of vancomycin resistance development. In Phase I, a peptidyiphosphonate antigen will be synthesized in which the substrate ester is replaced by a tetrahedral phosphorate ester and used to develop monoclonal antibodies in mice. The antibodies will be tested for their ability to break down the ester bond in the cell wall component D-Ala-D-lactate used by the vancomycin-resistant bacteria in place of the D-Ala-D-Ala of normal bacteria. A novel line of potential human therapeutics will be created in Phase II by genetic engineering to humanize the mouse monoclonal antibodies. The approach of using unique cell wall components as substrates to develop catalytic antibodies solves a challenge in dealing with antibiotic resistance that does not lend itself to traditional approaches using chemical analogs. PROPOSED COMMERCIAL APPLICATION: Humanized forms of catalytically active antibodies against D-Ala-D-lactate will be used initially to treat patients who no longer respond to vancomycin. Subsequently, the chemically synthesized antigen (or anti-idiotype antibodies produced in patients) may be used as an active immunogen for the more than 1 million patients who develop resistance of vancomycin.
