In vancomycin-resistant enterococci some of the normal cell wall D-Ala-D-Ala termini are substituted by D-Ala-D-Lac. As a result, vancomycin's efficacy is diminished over 1000-fold, and the bacteria becomes resistant to the effect of this last-resort drug. We hypothesized that cleaving the altered cell wall component with a small molecule will revert the bacteria sensitive to vancomycin. To test our hypothesis we have developed a fast assay and screened 300,000 combinatorial peptidic library compounds for their ability to cleave the termini of bacteria peptidoglycan precursors bearing D-Ala-D-Lac. Screening led to the identification of several structural requirements imperative for activity. These minimal structural requirements were assembled into simpler non-peptidic structures with the use of logical deduction and molecular modeling. Using this method, a small molecule that re-sensitized bacteria resistant to vancomycin was developed. This molecule catalytically and selectively cleaved the altered termini of bacteria cell wall precursors and reverted the antibiotic-resistance mechanism of Gram-positive bacterial pathogens. The work has been published in Science 2001 and was voted by the American Chemical Society as one of the top ten accomplishments in Genetics and Medicine for the year 2001 (list published in Chemical&Engineering News, December 2001). This strategy is further investigated with the goal of identifying clinically active agents of this action.