Chapter 34 – Design of Antibacterial Agents

The ‘design’ of a new antibacterial agent is utterly different from the design of a product in ‘macro’ engineering, such as aeronautical engineering. There is only a partial understanding of how the properties of the materials used in the design of an antibacterial agent (core structures, functional groups) determine its biological activities: from inhibitory potency at the bacterial target to bacterial cell envelope permeation to human pharmacokinetics, all of which are complex and multifactorial. Nevertheless, design elements can be used, including biophysically directed structure-based design. A case history is presented that describes the progression from a small compound or ‘fragment’ identified by nuclear magnetic resonance (NMR) as a relatively weak ligand of the GyrB protein of bacterial DNA gyrase to a derivative compound that displayed efficacy in an animal infection model and underwent phase 1 investigation in humans.