My lab is searching for antibiotics that inhibit bacterial primase and helicase. These DNA replication enzymes are special to the lagging strand during DNA synthesis. The factors that are driving our search are both the rising numbers of antibiotic-resistant bacterial strains and bioweapons such as Bacillus anthracis and Francisella tularensis. We are using numerous approaches including fluorescence resonance energy transfer (FRET), mass spectrometric peptide mapping, stopped-flow kinetics, computer-aided drug screening. and high-throughput screening of compound libraries.
The enzymes DnaG primase and DnaB helicase are excellent drug targets because they are found in all bacteria, are essential, and are very different from the primase and helicase found in humans. We have already identified the key, controlling step of primer synthesis and are now searching for inhibitors of this process. There appear to be several potential drug binding sites on both of these enzymes and we are now searching for the molecules that bind to those sites to inhibit their action.