Evolution and Prevention of Antibiotic Resistance: Small Molecule Inhibitors of Bacterial Recombination Enzymes

Antibiotic resistant bacteria are an ever-increasing problem for the modern chemotherapy of bacterial infectious diseases. The loss of effective antibiotic therapies due to antibiotic resistance and the withering antibiotic pipeline are resulting in a reemergence in deaths from bacterial infections. New strategies are needed to combat pathogenic bacteria and in this context bacterial targets involved in the development of resistance are emerging an intriguing candidates for inhibition studies. Recent evidence suggests that bacterial stress response pathways (i.e., SOS and competence for transformation) are responsible for accelerated genetic changes that ultimately establish antibiotic resistance. Intervening in these pathways by small molecule inhibition of key recombination enzymes, RecA and EndA, would impact the DNA repair, SOS mutagenesis and recombination-based horizontal gene transfer activities of these enzymes and hinder the acquisition of antibiotic resistance. Bacteria having loss-of-function mutations in the recA gene are more sensitive to antibiotic treatment and develop resistance more slowly or not at all. In addition, endA-null strains of S. pneumoniae have diminished transformation efficiencies and are unable to acquire resistance-conferring DNA. Therefore, we believe chemotherapeutic agents that impart these bacterial phenotypes could act synergistically with currently prescribed antibiotics to prevent the accumulation of populations that are resistant to them. Towards this goal, we sought to identify properly designed inhibitors of RecA and EndA. High-throughput screening (HTS) is recognized as a powerful tool in drug discovery to identify target-specific lead compounds. We developed rational high-throughput screening programs to discover small-molecule inhibitors of RecA and EndA. Through these studies, we have identified novel chemical classes that specifically target RecA or EndA and demonstrate that these enzymes hold potential as novel targets in the treatment of bacterial infections.Doctor of Philosoph