Special Challenges to the Rational Design of Antibacterial Agents

Abstract

The rational design of pharmaceutical agents with activity against bacterial targets presents several unique challenges due to the significant differences in the target bacterial cells and the eukaryotic cells of their mammalian hosts. The structural features and cellular components commonly targeted in drug design programs are often unique to bacteria. While this provides an excellent opportunity in terms of selectivity and decreased toxicities, there are also special factors that must be considered, including distribution to the target, bacterial cell penetration, efflux, metabolism and elimination, and the rapid emergence of bacterial resistance. These factors can play a key role in the design of compounds intended for use against bacterial targets and the application of traditional and nontraditional screening strategies aimed at identifying such compounds. This report discusses these special issues pertaining to antibacterial drug discovery, presents practical approaches to overcoming these challenges, and highlights some recent examples of their application. © 2013 Elsevier Inc.