Topoisomerase Inhibitors: Fluoroquinolone Mechanisms of Action and Resistance

Abstract

Quinolone antimicrobials are widely used in clinical medicine and are the only current class of agents that directly inhibit bacterial DNA synthesis. Quinolones dually target DNA gyrase and topoisomerase IV binding to specific domains and conformations so as to block DNA strand passage catalysis and stabilize DNA-enzyme complexes that block the DNA replication apparatus and generate double breaks in DNA that underlie their bactericidal activity. Resistance has emerged with clinical use of these agents and is common in some bacterial pathogens. Mechanisms of resistance include mutational alterations in drug target affinity and efflux pump expression and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes are commonly in a localized domain of the GyrA and ParC subunits of gyrase and topoisomerase IV, respectively, and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include other antimicrobials as well as quinolones. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is because of Qnr proteins that protect the target enzymes from quinolone action, a mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones.

Figure 1.

The rod-like structure of the QnrB1 dimer is shown (above) with the sequence of the monomer (below). The sequence is divided into four columns representing the four faces of the right-handed quadrilateral β-helix. Face names and color are shown at the top along with the naming convention for the five residues of the pentapeptide repeats. Loops A and B are indicated by one and two asterisks, respectively, with their sequences indicated below and the loops shown as black traces on the diagram. The carboxy-terminal α-helix is colored salmon. The molecular twofold symmetry is indicated with a black diamond. Type II turn containing faces are shown as spheres and type IV-containing faces as strands. N-term, Amino terminal; C-term, carboxy terminal. (From Jacoby et al. 2014; reproduced, with permission, from the authors.)