They are one of the most commonly prescribed classes of antibacterials globally and are used to treat a variety of bacterial infections in humans.
Due to these drugs’ widespread use (and overuse), the number of bacterial strains resistant to quinolones has been steadily growing since the 1990s.
As is the case with other antibacterial agents, the increased resistance to quinolones threatens the clinical utility of this important class of drugs. The quinolones act by converting their targets, gyrase, and topoisomerase into toxic enzymes that fragment the bacterial chromosome.
This review describes the development of quinolones as antibacterials, the structure and function of gyrase and topoisomerase, and the mechanical basis of the action of quinolones against their enzymatic targets.
Next, we will analyze the following three mechanisms that decrease the sensitivity of bacterial cells to quinolones:
The resistance mediated by the objective: is the most common and clinically significant form of resistance. Specific mutations cause it in gyrase and topoisomerase and weaken the interactions between the quinolones and these enzymes.
Plasmid-mediated resistance: is the result of extrachromosomal elements that encode proteins that interrupt the interactions between quinolones and enzymes, alter drug metabolism or increase the outflow of quinolones.
Chromosome-mediated resistance results from underexpression of porins or overexpression of cell efflux pumps, which decrease cell concentrations of quinolones.
Finally, this review will discuss recent advances in understanding how quinolones interact with gyrase and topoisomerase and how mutations in these enzymes cause resistance.
These latest findings suggest approaches for the design of new drugs that show improved activity against resistant strains.
Over a few decades, quinolones have been transformed from a small and unimportant class of drugs used primarily to treat urinary tract infections to some of the most commonly prescribed antibacterials in the world.
Today, they are used to treat many Gram-negative and Gram-positive bacterial infections. Unfortunately, the use of quinolones is threatened by the increasing emergence of resistance, which has been observed in all species treated with this class of drugs.
The cell targets for the quinolones are the bacterial type topoisomerases, gyrase, and topoisomerase. Recent work has helped define how quinolones interact with these enzymes and how mutations in gyrase or topoisomerase can lead to resistance.
In addition, additional resistance mechanisms caused by altered protein interactions, drug metabolism, uptake and outflow have been described.
In this review, we will analyze our current knowledge about the mechanism and resistance of quinolones and how this information can be used to design drugs capable of overcoming the most common forms of resistance.
Gyrase and topoisomerase generate double-stranded breaks in the bacterial chromosome to carry out its critical physiological functions.
Therefore, while they are essential for cell survival, these enzymes have the potential to fragment the genome. Quinolones take advantage of this last and potentially lethal characteristic cell and kill by increasing the concentration of the enzyme.
Therefore, these drugs are called ” topoisomerase poisons ” because they convert the gyrase and the topoisomerase into cellular toxins. In contrast, “catalytic inhibitors” block the overall catalytic functions of these enzymes without increasing the levels of DNA strands being broken.
Quinolones bind non-covalently at the enzyme-DNA interface at the active site of cleavage ligation. The drugs interact with the protein and are interspersed in the DNA in split excised bonds.
Because the cleavable bonds in each chain are staggered, two drug molecules are required to increase the levels of double-stranded DNA breaks. As a result of their intercalation, the quinolones increase the concentration in the steady-state of the cleavage complexes by acting as physical blocks for ligation.
Gyrase was identified for the first time as the cell target of the quinolones. The subsequent discovery of the topoisomerase raised whether this enzyme was also an objective for the quinolones.
Based on an analysis of strains of Escherichia coli carrying drug-resistant mutations in one, the other, or both enzymes, it was concluded that gyrase is the main toxic target for quinolones and that topoisomerase IV is a secondary target of the drug.
According to this conclusion, quinolones are more potent against coli gyrase than topoisomerase and induce higher DNA gyrase cleavage complexes in cells.
Surprisingly, genetic studies in Streptococcus pneumonia found that topoisomerase, instead of gyrase, was the primary cellular target of ciprofloxacin.
This led to the concept that gyrase was the main target of the quinolones in Gram-negative bacteria but that the opposite was true in Gram-positive Species. However, later studies found that this paradigm was not maintained in many cases.
There are examples of Gram-positive bacteria in which gyrase is the main target of quinolones. In addition, in a given bacterial species, it has been shown that different quinolones have different primary targets.
Ultimately, the question of treatment with quinolones remains a matter of debate, and the relative contributions of gyrase versus topoisomerase to the action of quinolones need to be evaluated on a species-by-species drug-by-drug basis.