Chapter 13. Antibacterial Agents, Targets and Approaches

Abstract

Publisher Summary This chapter summarizes the recent approaches to search for more effective agents for the development of resistance to current antibacterial therapy. The chapter includes a discussion on the inhibition of DNA and protein synthesis, the interference of cell-wall formation, and miscellaneous items. DNA gyrase, an essential type II bacterial topoisomerase, is known to be the target of quinolone antibiotics in gram-negative bacteria. Recent studies in E. coli suggested that the N-terminal portion of the GyrA subunit was critical for quinolone action. DNA gyrase has been recently shown to be the target of quinolones in gram-positive organisms as well. Structure-activity studies have revealed no clear correlation between mammalian cell cytotoxicity and antibacterial activity, but trends have suggested that certain structural features could reduce mammalian cell cytotoxicity. Two series of benzonaphthyridines have been examined for antibacterial activity. Recent work has indicated that DNA gyrase may also be the target of several naturally occurring antibiotics. The most widely used compounds currently available clinically are the cell-wall inhibitors such as the β-lactams and glycopeptides. The success of these inhibitors underscores the essential nature and attractiveness of the cell wall as an antibacterial target. In addition to targeting resistance in staphylococcus, β-lactam research has also focused on improving potency against pseudomonas and enferobacter. In the penicillins, the catechol-containing compound had outstanding activity against fseudornonas and stability to gram-negative β-lactamases. In addition to the traditional enzymes in cell-wall biosynthesis, several possible targets in peptidoglycan assembly have been identified for further exploitation. The use of agents that affect protein synthesis continues to play an important role in the chemotherapy of infectious diseases. New information regarding the interaction of the aminoglycosides with their ribosomal targets has renewed interest in this drug class.