Fluoroquinolone Antibiotics: Definition, Mechanism and Research

What are fluoroquinolones?

Fluoroquinolones are a large class of synthetic antimicrobials that contain a quinolone core ring and are attached to fluorogroups. The earliest quinolones did not contain fluorogroups (such as nalidixic acid) and were simply referred to as quinolones. In 1962, Lesher et al. accidentally discovered the first quinolone, nalidixic acid, while synthesizing the anti-malarial drug chloroquine. In the early 1980s, Koga et al. successfully developed 6-fluoro-7-piperazine-replaced norfloxacin (the first fluoroquinolone) by combining the structural characteristics of piperidol and flumequine. Studies have confirmed that fluorine atoms at C-6 position can enhance the inhibition effect of such compounds on DNA cyclase and improve the permeability of cell membrane, thus enhancing antibacterial activity, so the vast majority of quinolones used in clinical practice belong to fluoroquinolones.

Fluoroquinolones mechanism of action

Fluoroquinolones are characterized by their broad-spectrum antibacterial activity, targeting a range of Gram-positive and Gram-negative bacteria. Fluoroquinolones exert antibacterial activity by inhibiting bacterial topoisomerase IV and DNA gyroenzymes (members of the topoisomerase family). Inhibiting these enzymes can prevent normal DNA synthesis, replication, and division of bacteria, resulting in bacterial cell death. DNA spinase catalyzes the negative superhelix of circular bacterial DNA and relaxes the positive superhelix, which interferes with DNA replication. Topoisomerase IV unchains DNA after DNA replication, facilitating the separation of daughter cells. Inhibition of DNA cyclase is the main mechanism of killing Gram-negative bacteria, while inhibition of topoisomerase IV is mainly responsible for affecting Gram-positive bacteria.

Fluoroquinolone antibiotics list at BOC Sciences

Classification of fluoroquinolones

Fluoroquinolones are classified on the basis of their spectrum of activity.

Classification of fluoroquinolones. (Brar, R. K., 2020)

Fluoroquinolones uses

Fluoroquinolones are mainly used in clinical treatment of upper and lower respiratory tract infections, gastrointestinal infections, gynecological infections, sexually transmitted diseases, prostatitis, bone and joint infections, skin and soft tissue infections, etc. In addition to classical antibacterial activities, fluoroquinolones also have anti-tumor, anti-tuberculosis, anti-HIV, anti-malaria and anti-Alzheimer's disease and other non-classical biological activities, which have attracted widespread attention from pharmaceutical chemists.

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Resistance to fluoroquinolone

Fluoroquinolone resistance is a prominent problem, with some studies reporting increasing rates of resistance to fluoroquinolones in Gram-negative bacteria, including E. coli, over the past few decades. This is attributed to the widespread use of fluoroquinolones and the use of dosing regimens that select the development of resistant mutant strains. Fluoroquinolone use can also lead to bacterial resistance to other antimicrobial agents, including resistance to carbapenems in Pseudomonas aeruginosa and Enterobacteriaceae, and resistance to methicillin in human isolated Staphylococci.

Mechanisms by which bacteria develop resistance to fluoroquinolones include increased effluence and changes in antimicrobial targets: DNA rotase and topoisomerase IV. Specifically, point mutations in bacterial genes encoding the gyrA subunit of the DNA rotatase and the parC subunit of the topoisomerase were most common, resulting in reduced drug affinity for these complexes. Plasmid-mediated resistance to fluoroquinolones has been documented, and plasmids may develop resistance to multiple antimicrobials, leading to the emergence of multidrug-resistant bacteria. The protective measures selected against E. coli mutants require AUC24/MPC > 39 for ciprofloxacin and enrofloxacin and AUC24/MPC > 32 for marbofloxacin. Based on published pharmacological data, enrofloxacin administration at the lower end of the dose range appears to be more likely to select for the generation of resistant E. coli mutants. In addition, other studies support the use of doses with a high dose range, not only for enrofloxacin, but also for all veterinary fluoroquinolones to prevent resistance from developing in other bacterial species. To minimize further development of fluoroquinolone resistance, fluoroquinolones should not be used as first-line antibiotics for infections that may be sensitive to "inefficient" antibiotics, and antibiotics should be used with caution.

The introduction of large substituents to C-7 of quinolones can not only improve the anti-anaerobic activity, but also make quinolones difficult to be excreted by efflux running proteins, and reduce the probability of drug resistance in wild strains.

How toxic are fluoroquinolone antibiotics?

Despite their therapeutic benefits, fluoroquinolone antibiotics raise concerns regarding toxicity and adverse effects. Reports indicate potential risks, including tendon damage, particularly in older adults and those on concurrent corticosteroid therapy. Neurological effects, such as seizures and peripheral neuropathy, have also been associated with these drugs. Moreover, the risk of severe gastrointestinal side effects, such as Clostridium difficile infection, must be considered.

Fluoroquinolones can rapidly affect the chemical composition of tendon structures by depleting the levels of glycosaminoglycans (GAGs-compounds essential for the elasticity and integrity of structural tissues) in the tendons. In another study in mice, the researchers looked at the tendon healing ability of mice treated with the fluoroquinolone drug fleroxacin before tendon surgery, and the treated mice healed significantly less after surgery compared to control mice that did not receive fleroxacin, in addition to a significant reduction in the cross-sectional area of the tendons in the treated mice, the researchers concluded, Fluoroquinolone treatment has had a negative impact on tendon healing, which may have an impact on athletes undergoing tendon surgery/repair in the months following fluoroquinolone treatment.

Recent advances in fluoroquinolone research

Fluoroquinolone antibiotics are photochemically active

Lu et al. found that fluoroquinolone antibiotics (FQs) have similar photochemical activity to dissolved natural organic matter (DOM). This photochemical activity is derived from the quinolone chromophore in the molecule. The NORF and OFLO molecules themselves are not stable under light, however, during the photolysis of NORF and OFLO, their core quinolone structures remain intact, and these products largely inherit their parent's photochemical activity. The researchers speculate that other quinolone antibiotics may have similar photochemical activity due to the same chromophore. Therefore, once these antibiotics enter the surface water, a series of active substances such as ³FQs*, ¹O₂ and •OH can be produced under light, thus affecting the conversion and conversion of other organic and inorganic components in the surface water. And this effect persists even after the FQs parent molecule is photolysis. Therefore, pollutants that are susceptible to DOM photosensitization are also degraded by the presence of FQs. The interpretation of the reactivity of FQs as a photosensitizer in this study promotes the understanding of the water environmental behavior of FQs.

CH2-linked quinolone-aminopyrimidine hybrids

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to a variety of different types of antibacterial drugs such as fluoroquinolones, β-lactam, macrolides, also known as "superbacteria". The infection caused by it is difficult to control, which brings a very serious challenge to clinical treatment. At present, vancomycin is the gold standard for the treatment of MRSA infection and has been likened to the "last line of defense" for the treatment of MRSA infection. However, with the emergence of vancomycin-mediated MRSA and vancomycin-resistant MRSA, vancomycin sensitivity is gradually decreasing.

In 2020, Dai et al. of Fudan University used the "molecular hybridization" design strategy to obtain a class of oxygen-linked quinolone-pyrimidine antibacterial hybrids. These hybrids have strong anti-MRSA activity and no cross-resistance with existing fluoroquinolone antibiotics, and the anti-MRSA activity of the fluorine-free hybrid at C-6 of the quinolone parent nucleus is better than that of the corresponding C-6 fluorine-containing hybrid. Among them, the hybrid 15m has the characteristics of low toxicity, high activity, strong resistance to drug, and is not easy to induce drug resistance, which is worthy of further study. This work suggests that antimicrobial molecular design strategies can be used to improve resistance and avoid cross-resistance with existing fluoroquinolone antibiotics by introducing side chains that interact with DNA in the bacterial target enzyme /DNA complex at C-7 of the parent quinolone nucleus.

References

1. Brar, R. K., et al. Fluoroquinolone antibiotics: An overview. Adesh University Journal of Medical Sciences & Research. 2020, 2(1): 26-30.
2. Lu, J., et al. Fluoroquinolone antibiotics sensitized photodegradation of isoproturon. Water Research. 2021, 198: 117136.
3. Dai, H.,et al. Identification of CH2-linked quinolone-aminopyrimidine hybrids as potent anti-MRSA agents: Low resistance potential and lack of cross-resistance with fluoroquinolone antibiotics. European Journal of Medicinal Chemistry. 2024, 271: 116399.