Chapter 20: Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE)

The discovery of new antibacterials to combat the emergence of resistant organisms is of global importance. One strategy to reduce the development of resistance in new drugs is to identify a single pharmacophore that has the ability to target more than one essential bacterial enzyme. This opportunity has already been realised with certain drugs from the quinolone/fluoroquinolone class of antibiotics, and these drugs act via the GyrA and ParC subunits on the bacterial type II topoisomerases DNA gyrase and topoisomerase IV. This class of enzymes also presents a second opportunity for single pharmacophore multi-target inhibitors as they contain similarly conserved binding sites on the GyrB and ParE subunits which are responsible for the hydrolysis of ATP, a critical step in these enzymes’ function. Competitive inhibitors of ATP have been shown to inhibit both GyrB and ParE and to reduce spontaneous resistance in vitro which is indicative of dual-target action. This chapter will focus on one chemical class of dual-targeting DNA gyrase and topoisomerase IV inhibitors, the ethyl ureas, and will present some of the preclinical data supporting their mechanism of action as a novel series of antibacterials.