Picking pockets to fuel antimicrobial drug discovery

The inhibition of essential enzymes in microbial pathogens offers a route to treatment of infectious diseases. However, although the biology of the organism dictates a need for a particular enzyme activity, this does not necessarily mean that the enzyme is a good drug target. The chemistry of the active site (size, shape and properties) determines the likelihood of finding a molecule with the right properties to influence drug discovery. Discriminating between good and less-good targets is important. Studies on enzymes involved in the regulation of oxidative stress and pterin/folate metabolism of trypanosomatid parasites and isoprenoid precursor biosynthesis in bacteria and apicomplexan parasites illustrates a range of active sites representing those that are challenging with respect to the discovery of potent inhibitors, to others that provide more promising opportunities in drug discovery.