QUINOLONES: MECHANISM OF ACTION AND CLASSIFICATION - MEDICINE - 2025

The quinolones are a group of synthetic pharmaceutical agents with bacteriostatic and bactericidal widely used in the treatment of infections in both human and veterinary medicine. It is a drug completely synthesized in the laboratory.

This differentiates it from classic antibiotics such as penicillin, where the entire molecule (penicillin) or a good part of it (semi-synthetic penicillins) is produced by a living being (in the case of penicillin, a fungus). Quinolones have been in use since the 1960s, and have evolved over the decades.

Within the framework of this evolution, changes have been introduced in its molecular structure, increasing its effectiveness, increasing its potency and expanding its spectrum of action.

Quinolones have been divided into several 'generations', each one differentiated from the previous one by subtle changes in its structure, but with great impact on its clinical applications.

Mechanism of action

Quinolones exert their bactericidal action by interfering with DNA duplication in bacterial cells.

For bacteria to be viable, constant DNA duplication is necessary to allow bacterial replication. Likewise, it is essential that the DNA strands separate almost constantly to allow the transcription of RNA and, therefore, the synthesis of different compounds essential for the life of the bacterium.

Unlike the eukaryotic cells of higher organisms, where DNA develops less frequently, in bacterial cells it is a process that occurs constantly; therefore, by interfering in the mechanisms that regulate the process, it is possible to end cell viability.

To achieve this, quinolones interact with two fundamental enzymes in DNA replication: topoisomerase II and topoisomerase IV.

Inhibition of topoisomerase II

During the DNA replication process, its double helix structure unwinds in segments. This causes "supercoils" to form beyond the area where the molecule is separated.

The normal action of topoisomerase II is to "cut" both strands of DNA at the point where the positive supercoil is formed, in turn introducing segments of DNA with negative supercoil to relieve tension on the molecular chain and help it maintain its topology. normal.

At the point where the strands with negative turns are introduced, ligase acts, which is able to join both ends of the cut chain through an ATP-dependent mechanism.

It is precisely in this part of the process that quinolones exert their mechanism of action. Quinolone interposes between DNA and the topoisomerase II ligase domain, establishing molecular bonds with both structures that literally "lock" the enzyme, preventing the DNA from rejoining.

DNA strand fragmentation

By doing this, the DNA strand - which must be continuous for the cell to be viable - begins to fragment, making cell replication, DNA transcription and the synthesis of compounds by the cell impossible, which ultimately leads to their lysis (destruction).

Binding to topoisomerase II is the main mechanism of action of quinolones against gram negative bacteria.

However, the introduction of chemical modifications in the most recent generations of this drug have allowed the development of molecules with activity against gram positive bacteria, although in these cases the mechanism of action is based on the inhibition of topoisomerase IV.

Inhibition of topoisomerase IV

Like topoisomerase II, topoisomerase IV is capable of separating and cutting the DNA double helix, but in this case no negatively wound segments are introduced.

Topoisomerase IV is vital in bacteria negative for cell duplication, since the DNA of the "daughter bacteria" remains attached to that of the "mother bacteria", being the function of topoisomerase IV to separate both strands at the exact point to allow that both cells (parent and daughter) have two exactly the same copies of DNA.

On the other hand, topoisomerase IV also helps to eliminate supercoils caused by the separation of DNA strands, although without introducing strands with negative turns.

By interfering with the action of this enzyme, quinolones not only inhibit bacterial duplication but also lead to the death of the bacteria in which a long strand of non-functional DNA accumulates, making it impossible for it to fulfill its vital processes.

This is particularly useful against gram positive bacteria; Hence, intensive work has been done to develop a molecule capable of interfering with the action of this enzyme, something that was achieved in the third and fourth generation quinolones.

Classification of quinolones

Quinolones are divided into two large groups: non-fluorinated quinolones and fluroquinolones.

The first group is also known as first generation quinolones and has a chemical structure related to nalidixic acid, this being the type molecule of the class. Of all the quinolones, these are the ones with the most restricted spectrum of action. Nowadays, they are rarely prescribed.

In the second group are all quinolones that have a fluorine atom in position 6 or 7 of the quinoline ring. According to their development, they are classified into second, third and fourth generation quinolones.

Second generation quinolones have a broader spectrum than first generation quinolones, but still restricted to gram negative bacteria.

For their part, the third and fourth generation quinolones were designed to also have an effect on gram positive germs, which is why they have a broader spectrum than their predecessors.

Here is a list of the quinolones that belong to each of the groups. At the top of the list is the typical antibiotic of each class, that is, the best known, used and prescribed. In the rest of the positions the lesser known molecules of the group are named.

First generation quinolones

- Nalidixic acid.

- Oxolinic acid.

- Pipemidic acid.

- Cinoxacin.

The first generation quinolones are currently used only as urinary antiseptics, since their serum concentrations do not reach bactericidal levels; therefore, they play an important role in the prevention of urinary infections, especially when instrumentation procedures are to be performed on it.

Second generation quinolones

- Ciprofloxacin (perhaps the most widely used quinolone, especially in the treatment of urinary infections).

- Ofloxacin.

Ciprofloxacin and oflaxin are the two main representatives of second-generation quinolones with bactericidal effect, both in the urinary tract and in the systemic field.

Lomefloxacin, norfloxacin, pefloxacin and rufloxacin are also part of this group, although they are used less frequently since their action is mainly limited to the urinary tract.

In addition to activity against gram-negative bacteria, second-generation quinolones also have an effect against some Enterobacteriaceae, Staphylococci, and, to some extent, Pseudomonas aeruginosa.

Third generation quinolones

- Levofloxacin (known to be among the first quinolones with an effect against streptococci and formally indicated in respiratory infections).

- Balofloxacin.

- Temafloxacin.

- Paxufloxacin.

In this group of antibiotics, preference was given to activity against gram positives, sacrificing activity against gram negatives somewhat.

Fourth generation quinolones

The typical antibiotic of this group is moxifloxacin, which was designed with the aim of combining in a single drug the classical anti-gram negative activity of the first and second generation fluoroquinolones with the anti-gram positive activity of the third generation.

Together with moxifloxacin, gatifloxacin, clinafloxacin and prulifloxacin were developed as part of this group; All of these are broad-spectrum antibiotics with systemic activity against gram negatives, gram positives (streptococci, staphylococci), atypical bacteria (chlamydia, mycoplasma), and even P. aeruginosa.

References

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