Quinolones are one the most commonly prescribed classes of antibacterials in the world and are used to treat a broad variety of Gram-negative and Gram-positive bacterial infections in humans. However, because of the wide use (and overuse) of these drugs, the number of quinolone resistant bacterial strains has been growing steadily since the 1990s. As is the case with other antibacterial agents, the rise in quinolone resistance threatens the clinical utility of this important drug class. 

Quinolones target the bacterial type II topoisomerases, gyrase and topoisomerase IV. These enzymes regulate DNA under- and over-winding and remove knots and tangles from the genome. Gyrase and topoisomerase IV create transient double-stranded breaks in the genetic material in order to carry out their essential cellular functions. Quinolones take advantage of this enzyme-mediated DNA cleavage activity and kill cells by converting gyrase and topoisomerase IV, into toxic “nucleases” that fragment the bacterial chromosome.

Quinolone resistance is most often associated with mutations at two highly conserved amino acid residues (a serine and an acidic residue) in gyrase and/or topoisomerase IV. Recent structural and biochemical studies have determined how these two residues facilitate drug-enzyme interactions. Quinolones contain a keto acid group that chelates a non-catalytic Mg2+ ion, which in turn is coordinated by four water molecules. Two of these water molecules are situated close enough to the serine and acidic residue to form hydrogen bonds. For clinically relevant quinolones, this “water-metal ion bridge” serves as the primary interaction between the drug and the bacterial type II topoisomerases.

Dr. Osheroff’s talk will provide background on DNA topology and type II topoisomerases. It will go on to describe experiments that led to the discovery of the water-metal ion bridge and defined its role in mediating quinolone-enzyme interactions. The talk will describe how this knowledge has been used to design novel quinolones and quinolone-based drugs that overcome resistance. Finally, it will discuss recent experiments with novel naphthyridone-based drugs that alter gyrase-mediated DNA cleavage by a unique mechanism and retain their activity against quinolone-resistant mutant enzymes.