Chemical properties of antimicrobials and their uniqueness

Abstract

Antibacterial drug discovery has benefitted from the availability of a large number of genome sequences for target selection and new assay formats for inhibitor identification. Until recently, however, little consideration was given to the chemical properties of the compounds screened against these targets. Most screening campaigns have been performed with compound libraries that are ill suited for antibacterial lead optimization. Antibacterial agents occupy a different region of physicochemical property space than compounds from other drug classes. In particular, the structural complexity of antimicrobials is generally greater, with an increased density of polar functionality, a larger number of chiral centers, and a higher molecular weight. These unusual chemical properties are a function of the cellular penetration requirements and the pharmcodynamic behavior of antibacterial drugs, among other factors. The optimal compound library for screening against antibacterial targets would consist of natural products and synthetic chemicals designed to inhabit a similar region of chemical property space as natural products.