Application of SBDD to the Discovery of New Antibacterial Drugs

The emergence of bacteria that are multiply resistant to commonly used antibiotics has created the medical need for novel classes of antibacterial agents. The unique challenges to the discovery of new antibacterial drugs include the following: spectrum, selectivity, low emergence of new resistance, and high potency. With the emergence of genomic information, dozens of antibacterial targets have been pursued over the last 2 decades often using SBDD. This chapter reviews the application of structure-based drug design approaches on a selected group of antibacterial targets (DHFR, DHNA, PDF, and FabI) where significant progress has been made. We compare and contrast the different approaches and evaluate the results in terms of the biological profiles of the leads produced. Several common themes have emerged from this survey, resulting in a set of recommendations.