Mechanism of Action of and Resistance to Quinolones

David T. Bearden, PharmD, and Larry H. Danziger, PharmD

Disclosures

Pharmacotherapy. 2001;21(10s) 

In This Article

Mechanisms of Quinolone Resistance

Bacterial Topoisomerase Mutations

Quinolones inhibit the action of DNA gyrase and topoisomerase IV and kill bacteria by binding to these enzyme-DNA complexes, thereby disrupting DNA replication.[11] Mutations in the genes that encode for DNA gyrase and topoisomerase IV can change the structure of one or more subunits of these enzymes. These mutations generally occur in a discrete sequence of the bacterial genes, called the quinolone resistance determinant region.[12] Structural changes in type II topoisomerase subunits can inhibit the ability of quinolones to bind at these sites of action.[8] Altered binding can decrease the drugs' effectiveness in inhibiting bacterial DNA replication and raise bacterial minimum inhibitory concentrations (MICs).

Membrane Permeability and Efflux Pumps

In addition to alterations in DNA gyrase and topoisomerase IV, mutations occur in the outer and inner membrane proteins of bacteria. Quinolones must pass through cell membranes to reach their topoisomerase targets. The degree to which they cross cell membranes varies with bacterial species. The outer membranes of certain gram-negative organisms, including Pseudomonas aeruginosa, limit the uptake of fluoroquinolones.[13] Altered expression of outer cell membrane channels (porins) may limit the agents' ability to permeate membranes of gram-negative bacteria.[14]

Other resistance mechanisms involve development and expression of efflux pumps that transport quinolones and other antibiotics out of the cell.[15] A combination of intrinsic lack of permeability, alterations in porin expression, and efflux mechanisms is often involved in resistance.[13,16,17]

Acquisition of Resistance

Chromosomally mediated changes caused by point mutations in genes are the greatest single cause of quinolone resistance.[15] Plasmid-mediated mechanisms have been reported[18] but are not well elucidated. Induction of resistance to a quinolone involves production of a gene mutation. Spontaneous mutations conferring various levels of resistance are thought to occur at a frequency of 106-1010 cell divisions. The four genes involved in type II topoisomerase production are the focus of much interest in quinolone resistance. Mutations in gyrA and gyrB and parC and parE genes have variable effects on MICs in different species of bacteria.[19,20,21,22] Mutations conferring resistance typically occur in a stepwise manner. Spontaneous mutations create a small mutant population with decreased susceptibility to quinolones. Exposure to inter-mediate quinolone concentrations can inhibit susceptible strains and allow overgrowth of a resistant first-step mutant. Second mutations then occur in first-step mutants, further raising MICs. This process can continue and augment other mechanisms, such as decreased permeability or efflux.

Low-level resistance, with MICs in the intermediate breakpoint range, can be conferred by a number of single mutations. High-level resistance, with MICs above the established breakpoint, typically is seen with acquisition of multiple-resistance mechanisms.[15] There are many examples of combined resistance mechanisms. A simultaneous mutation involving two different segments of gyrA may exhibit increased MICs.[23] Combined alterations can occur in both DNA gyrase and topoisomerase IV that affect resistance.[24] In addition, dual mutations involving an efflux pump and DNA gyrase can decrease bacterial susceptibility.[25]

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