Towards catalytic fluoroquinolones

The appearance of bacterial strains resistant to multiple antibiotics has encouraged an extensive drive towards the goal of slowing down resistance development. One strategy is catalytic antibiotics, which seeks to mediate catalytic inactivation of the therapeutic target to form an inactive or dysfunctional entity (Fig. 1a). The possible benefits of this approach include: (i) increased potency, (ii) activity against resistant bacteria and (iii) reduced potential for the development of new resistance. Based on published structural and mechanistic data about the topoisomerase IIA-DNA complex (the target of fluoroquinolone antibiotics) and about artificial nuclease systems, we have used molecular docking to rationally design several ciprofloxacin-nuclease analogues (Fig. 1b) with the potential to cleave phosphodiester bonds within the bacterial topoisomerase IIA-DNA complex, in such a manner as to cause bacterial chromosome fragmentation in a catalytic fashion. These ciprofloxacin-nuclease agents contain a Cu(II)-cyclen or Co(III)-cyclen system, a guanidine system or both of these systems, linked via a hydrophobic linker to the piperazine ring of ciprofloxacin, and are designed to catalyse DNA hydrolysis by leaving group activation, phosphate group stabilization, intramolecular-nucleophilic activation, or a combination thereof. The design, synthesis and preliminary biological evaluation of selected new designer structures will be presented.