Mini Review: Is fluoroquinolone drug or poison?

2.1. First generation

In 1962, Lesher G. Y. and his collaborators presented the primary derivative of quinolone, nalidixic acid, which has direct action against Gram-negative bacteria and has been utilized to treat urinary tract diseases. Within the taking after a long time, a wide extend of products derived from common components were synthesized, which might be gathered by: cinoline (cinoxacin), pyrido-pyrimidine (pipemidic acid, piromidic acid), naphthyridine (nalidixic corrosive) and quinolones (oxolinic acid, miloxacin, tioxacin, etc.). These derivatives, with separated structures, have two common pharmacological properties:

– A fine antibacterial range, extraordinarily planned for Enterobacteriaceae;

– A pharmacokinetics that permits quick disposal and diminished tissue intrigued, as it were permitting them to be utilized as urinary cleaning agents [5].

Fig. 3Quinolones of first generation

The victory of early era quinolones fortified inquire about in this zone, which driven to the blend getting, after 1980, of a unused series of compounds with solid antibacterial properties and a large range of antibacterial movement that included Gram-positive and Gram negative.

2.2. Second generation

Koga and his collaborators presented Norfloxacin in clinical utilize in 1980, the primary quinolone with a fluorine atom substituted within the C-6 position and a C-7 piperazine. Norfloxacin was the primary quinolone with expanded antimicrobial action, acting on a wide range of Gram-positive and Gram-negative microscopic organisms, counting Pseudomonas aeruginosa microorganisms [6].

Fig. 4Quinolones of second generation

Investigate within the field of derivatives with a quinolone structure has driven to modern compounds gotten, which have been classified as third and fourth era systemic quinolones, generally compelling against Staphylococcus aureus. Their wide antibacterial range incorporates anaerobes, Chlamydia and Mycoplasma [7].

2.3. Third generation

Third-generation agents currently include levofloxacin, grepafloxacin, and sparfloxacin. These agents are separated into a third class because of their expanded action against gram-positive organisms, counting the penicillin-resistant Streptococcus pneumoniae [8].

2.4. Fourth generation

The fourth generation has the taking after common angles: an indistinguishable instrument of activity by the restraint of DNA gyrase A subunit, solely chromosomal resistance of microbes and certain impacts of comparative microbes: photo-toxicity, neurotoxicity, cartilage harmfulness [9].

So far, a huge number of antibacterial substances having a place to the class said over has been utilized in medication. Quinolones are utilized when treating urinary tract diseases, respiratory tract, intestinal contaminations, ear/nose/throat infections, tissue contaminations and mellow skin, meningitis caused by gram-negative microbes and Staphilococci microscopic organisms, infections of the liver and bile channels, sepsis and endocarditis, prophylaxis and surgical diseases and on patients with safe lack.

Fig. 5Quinolones of third generation

Fig. 6Quinolones of fourth generation

3.1. Intra-bacterial penetration

Gram (+) bacteria lack an outer membrane, with a wall consisting of a thick peptidoglycan. The penetration of quinolones is by passive diffusion.

For bacteria with gram (–), the intrabacterial penetration is done by two ways:

– The porin pathway: hydrophilic channels in the form of trimers for hydrophilic and small quinolones (< 400 dalton) (norfloxacin and ciprofloxacin).

– The lipopolysaccharide (LPS) pathway: by Mg2 + chelation associated with LPS and discovery of hydrophobic zones, hence the penetration of hydrophobic quinolones (sparfloxacin) [10].

3.2. Mechanisms of quinolone action

QNs interfere with changes in DNA supercoiling by binding to II or IV. This leads to the formation of double-stranded DNA breaks and cell death either in a protein synthesis dependent manner or in a manner independent of protein synthesis [11]. They target two parent enzymes belonging to the family of topoisomerases II and which are involved in the synthesis of bacterial DNA: DNA-gyrase (generally the main target in Gram-negative bacteria) and topoisomerase IV (usually the main target in Gram-positive bacteria).

New fluoroquinolones such as gatifloxacin and moxifloxacin have both activities. DNA Gyrase is composed of two GyrA subunits encoded by the gyrA gene and two GyrB subunits encoded by the gyrB gene. It introduces a negative supercoiling into the bacterial DNA double helix upstream of the replication fork. This activity is essential for the initiation of bacterial DNA replication and for transcription [12, 13].

Topoisomerase IV has a decatenation activity that allows the separation of replicated chromosomes at the end of a replication sequence. It is composed of 4 subunits homologous to those of gyrase, two ParC subunits (homologues of GyrA) and two ParE subunits (homologues of GyrB) encoded by the genes parC and parE respectively [14].

3.3. Mechanisms of quinolone resistance

As for many antibiotics, the resistance goes through two main mechanisms: reduction of the intrabacterial concentration of the antibiotic and alteration of its target enzymes. For the latter mechanism, it is in fact mutations in genes encoding DNA gyrase and topoisomerase IV. This type of mutation is stable and spread easily in the bacterial environment. The clinical resistance appears according to a mechanism in step of staircase by accumulation of several genetic mutations. This can induce class resistance to all quinolones, or only certain family molecules.

Here again, the presence of a methoxy group in the 8-position, as for moxifloxacin and gatifloxacin, is important since it reduces the probability of selection of mutant resistant [15-18]. As for reducing the concentration of antibiotics in the bacteria, it can involve several mechanisms, including changes in the external bacterial membrane, such as the modification of protein structures called porins, which provide a part of the exchanges between the outside and the outside. inside the bacteria. Since these exchange systems are not specific for the molecules transported, the acquisition of this type of resistance can also lead to a reduction in sensitivity to other classes of antibiotics, notably carbapenems [15].

The reduction of the concentration of quinolones in the bacterium can also be the consequence of the increase in its output, by a so-called efflux system. This mechanism can either make the bacterium resistant to the antibiotic itself if it is very powerful, or allow the bacterium to survive in a suboptimal concentration of antibiotics, which ultimately promotes the appearance of genetic mutations in the body. made of a major pressure of antibiotic selection then playing at its maximum efficiency. It is therefore in all cases a mechanism promoting resistance to quinolones, and its low specificity tends to allow the emergence of multiresistance.

Finally, quinolone resistance can also be transmitted by plasmids. However, this phenomenon well described in Klebsiella sp. and Escherichia coli appear to be rare for other bacterial families, except in certain geographic areas such as East Asia [19].