Chapter 5 : Antibiotics That Block DNA Replication and Repair: the Quinolones

Abstract:

Inhibition of DNA replication and repair enzymes would seem a logical target for antibacterial action by natural products elaborated by microbes to kill their neighbors. One such class of molecules, the coumarins, represented by such streptomycete metabolites as novobiocin and coumermycin, has been studied for many years and served to pinpoint enzymes called DNA type II topoisomerases, specifically DNA gyrase, as the killing target. The newest generation of quinolones in particular, such as gatifloxacin, have increased potency against gram-positive pathogens. Thousands of fluoroquinolones have been synthesized around the core planar heterocyclic nucleus that gives the family its name. Extensive analysis has indicated that quinolones affect the double-strand cleavage/double-strand religation equilibrium in gyrase and topo IV catalytic cycles, such that the cleaved complex accumulates. There has been speculation about whether quinolones speed up the double-cleavage step of bound DNA or selectively slow the double-religation step, without definitive evidence for either interpretation. The mechanism by which quinolones induce the accumulation of the doubly cut covalent DNA-enzyme intermediate is likewise still mysterious. As the quinolone-covalent gyrase-doubly cut DNA intermediate accumulates, the killing action is thought to be from the downstream effect this block has on the progression of DNA replication forks which are halted by this. It may be that DNA repair machinery is recruited, attempts to come to the rescue, and fails as the recalcitrant quinolone-stabilized gyrase-DNA intermediate persists. This may be the signal that turns on the signaling processes that lead to the rapid killing of bacteria induced by the quinolones.