• Quinolones

  Quinolones:  Audio Overview

  • Quinolone antibiotics (especially the fluoroquinolones) are a class of synthetic, broad-spectrum antibacterials originally derived from nalidixic acid.

    • These drugs have become important agents in human medicine due to their potent bactericidal activity, excellent oral bioavailability, and broad tissue penetration.¹

     

  • "Fluoroquinolones | 2nd vs 3rd vs 4th Generation | Targets, Mechanism of Action"

    Attribution JJ Medicine Lesson on Fluorquinolone antibiotic ciprofloxacin vs. levofloxacin vs. moxifloxacin https://www.youtube.com/@jjmedicine https://www.youtube.com/watch?v=suoPHa2z4L4 (March 18, 2019)

  • Mechanism of Action

    • Quinolones occupy a distinctive position in antimicrobial therapy through their direct inhibition of bacterial DNA synthesis.^2,3 

    • Unlike other antibiotic classes that target cell wall synthesis or protein production, quinolones specifically target two essential bacterial enzymes: DNA gyrase and topoisomerase IV.^3,4,5

    • DNA-Gyrase and topoisomerase IV our central for bacterial DNA replication transcription which makes of these enzymes important therapeutic targets.^3,6

      • Quinolones (including fluoroquinolones) are bactericidal agents targeting DNA replication.⁷ 

        • Bacterial DNA synthesis is inhibited by stabilizing DNA complexes of DNA with two essential bacterial enzymes: DNA gyrase (also known as topoisomerase II) and topoisomerase IV.¹ 

          • At the molecular level, quinolones “trap” gyrase or topoisomerase IV on DNA, forming a ternary complex that halts replication forks and generates lethal double-strand breaks when the blocked replication machinery collides with these complexes.^9,10

          • By binding to these enzymes, quinolones promote cleavage of bacterial DNA and prevent the resealing of the DNA strands, leading to fragmentation of the chromosome and rapid cell death.

          • Generally, Gram-negative antibacterial activity correlates with inhibition of DNA gyrase, whereas Gram-positive activity correlates with inhibition of topoisomerase IV.¹ 

      • Quinolones exhibit concentration-dependent killing, meaning their efficacy improves as drug concentration increases relative to the organism’s MIC (minimum inhibitory concentration) until the optimum bactericidal concentration is reached, after that the bactericidal activity declines.⁸

      • Peak bactericidal effect is typically observed when concentrations reach ~30× MIC.

        • Quinolones also produce a post-antibiotic effect which consists of continued bacterial growth suppression even after drug levels fall below the MIC, lasting roughly 1–2 hours.

          • These pharmacodynamic properties allow quinolones to be dosed once or twice daily for most infections.

      • Mechanism of Quinolone Action:  Summary

        Quinolones exert their bactericidal effect by targeting two essential bacterial enzymes known as type II topoisomerases: DNA gyrase and topoisomerase IV.2   These enzymes are homologous, with DNA gyrase consisting of GyrA and GyrB subunits and topoisomerase IV consisting of ParC and ParE subunits, but they perform distinct, vital roles in the cell.3 DNA Gyrase This enzyme is unique to bacteria and is responsible for introducing negative supercoils into the DNA helix.15   This process is critical for compacting the bacterial chromosome and, more importantly, for relieving the positive supercoiling (torsional stress) that builds up ahead of the replication fork as DNA unwinds.16   Without this action, DNA replication would quickly grind to a halt. DNA gyrase is a primary target of quinolones in most Gram-negative bacteria.17 Topoisomerase IV The primary function of this enzyme is decatenation—the unlinking of the two intertwined daughter chromosomes following DNA replication. This step is essential for the proper segregation of the chromosomes into daughter cells during cell division. Semiconservative replication of double-helical nature of DNA results in the two newly replicated DNA strands to be interlinked. These links must be removed so that chromosome may segregate into daughter cells so that cell division can complete.18 The second function of in the cell of topoisomerase IV's is to relax positive supercoils. This role is shared with DNA gyrase, which is also able to relax positive supercoils. Gyrase and topoisomerase IV remove the positive supercoils which accumulate ahead of a translocating DNA polymerase, allowing DNA replication to continue unhindered by topological strain.18 Topoisomerase IV is a primary target of quinolones in many Gram-positive bacteria, such as Staphylococcus aureus.17

     

    • "Structure bacterial DNA-Gyrase complex with DNA and two ciprofloxacin molecules (green)"14

      "Quinolones are chemotherapeutic bactericidal drugs.14  They interfere with DNA replication by preventing bacterial DNA from unwinding and duplicating.11 Specifically, they inhibit the ligase activity of the type II topoisomerases, DNA gyrase and topoisomerase IV, which cut DNA to introduce supercoiling, while leaving nuclease activity unaffected. With the ligase activity disrupted, these enzymes release DNA with single- and double-strand breaks that lead to cell death.4 The majority of quinolones in clinical use are fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-8 position. The majority of quinolones in clinical use are fluoroquinolones, which have a fluorine atom attached to the central ring system, typically at the 6-position or C-8 position. Most of them are named with the -oxacin suffix. First and second generation quinolones are largely active against Gram-negative bacteria, whereas third and fourth generation quinolones have increased activity against Gram-positive and anaerobic bacteria.12 Some quinolones containing aromatic substituents at their C-7 positions are highly active against eukaryotic type II topoisomerase.13"14

      Unknown structure of DNA-Gyrase complexes ciprofloxacin (green) and DNA. Generated from 2 pdb entry 2xct with pymol. Attribution Fdardel, CC BY-SA 3.0 <https://creativecommons.org/licenses/by-sa/3.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:GyraseCiproTop.png

  • Antimicrobial Spectrum and Activity

    • Structure-Activity Relationships of Quinolones

      "The structure-activity relationships (SAR) of quinolones. "The antibacterial activity quinolones is improved with modifications of different substituents in different positions. "The color of the groups in the bracket correlates with the type of activities. Attribution Figure above corresponds to figure 2 of reference 2. Pham T Ziora Z Blaskovich M Quinolone antibiotics. Medchemcomm. 2019 June 28;10(10): 1719-1739. https://pmc.ncbi.nlm.nih.gov/articles/PMC6836748/

    • First-generation quinolones

      • Early quinolones (e.g. nalidixic acid) were mainly active against Enterobacteriaceae and other Gram-negative rods, with minimal systemic distribution, limiting them to urinary tract infections.¹

        • First-generation drugs included:

          • Nalidixic acid

          • Cinoxacin

          • Flumequine,

          • Oxolinic acid,

          • Piromidic acid

          • Pipemidic acid and 

          • Rosoxacin²⁰

        •  First Generation agents primarily cover Gram-negative bacilli such as E. coli, Klebsiella species and Proteus species in uncomplicated UTIs, and are not used for systemic infections.¹⁴ 

          • Three drugs were administered orally and exhibited low serum in tissue levels.

            • First-generation agents required frequent daily administration (four times daily) as well as an elevated tendency to select for resistant Gram-negative bacilli. They also exhibited limited or poor activity against Gram-positive bacteria as well as inducing photosensitivity reactions in patients. First generation quinolones had the potential to induce convulsions in patients with seizure disorders.¹⁹

          • They also exhibited narrow Gram-negative bacterial coverage.¹

    • Second-generation quinolones

      • Second generation agents including fluorine atom in their structure.

        • This modification resulted in improved antimicrobial activity against Gram-negative bacteria and extends it to some Gram-positive bacteria.¹⁴

        • Second generation fluoroquinolones targeted Gram-negative organisms including Pseudomonas aeruginosa as well as some Gram-positive bacteria extending to Staphylococcus aureus but not to Streptococcus pneumoniae as well as to some atypical pathogens.²¹

        • Second generation agents include ciprofloxacin, enoxacin, lomefloxacin, ofloxacin, fleroxacin, ofloxacin and rufloxacin. 

          • Of these, ciprofloxacin is the most potent fluorquinolone against P.aeruginosa.

            • Some second-generation quinolones may be useful in treating lower respiratory tract infections and acute sinusitis; however, S. pneumoniae is often resistant to these drugs.

              •  Accordingly, second-generation quinolones would not be drugs of first choice for lower respiratory tract infections or acute sinusitis. Among the second-generation drugs, ofloxacin exhibits highest activity against Chlamydia trachomatis.

              • The most widely used second-generation quinolones are likely ciprofloxacin and ofloxacin due to both oral and IV formulation as well as extensive FDA-labeled indication for use.²¹

            • Clinical use of second-generation agents include both uncomplicated and complicated urinary tract infections as well as pyelonephritis.

              • Other uses include treating sexually transmitted diseases, skin and soft tissue infections, and prostatitis.²¹

                • So, with respect to Legionella pneumophila, for example, ciprofloxacin exhibits good activity.²³ 

                • Good activity by ciprofloxacin is also noted against Pseudomonas aeruginosa as well.

                • So the main inadequacy is lack of coverage again Streptococcus pneumoniae,  meaning that ciprofloxacin administration would be inappropriate for management of community-acquired pneumonia.

                  • To summarize then, ciprofloxacin and ofloxacin would be expected effective in managing:

                    •  (1) Urinary tract infections caused by nonresistant bacteria,

                    • (2) Respiratory tract infections caused by susceptible Gram-negative bacteria,

                    • (3) Skin and soft-tissue infections and

                    • (4) Osteomyelitis [ciprofloxacin only].²³

    • Third-generation quinolones

      • Third-generation quinolones have properties similar to the second generation but add expanded Gram-positive coverage including penicillin-sensitive and penicillin-resistance Staphylococcus pneumoniae (S. pneumoniae).

        • The expansion of sensitive organisms targeted by third-generation quinolones, now including Gram-positive coverage of Streptococcus pneumoniae, now allowed quinolones to be a reliable option for empirical treatment of community acquired pneumonia.²³

        • In addition there is expanded coverage of atypical pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae.²¹

        • Notable clinical uses include community-acquired pneumonia as well as acute worsening of chronic bronchitis.²¹

      • Examples of third-generation quinolones include balofloxacin, grepafloxacin, levofloxacin, pazufloxacin, temofloxacin.

        • To summarize then, third-generation quinolones  would be expected effective in managing:

          • (1) Community-acquired pneumonia

          • (2) Bacterial exacerbations of acute bronchitis

          • (3) Urinary tract infections and

          • (4) Skin infections.²³ 

    • Fourth-generation quinolones²²

      • The fourth generation quinolones incorporated number of structural side chain modifications that:

        • Reduce quinolone efflux out of bacterial cells

        • Increase serum half-life

        • Increase potency against Gram-positive bacteria and

        • Add important anaerobic coverage.

          • Notable is a C-8 methoxy group that enhances potency while reducing toxicity.

      • An example of the fourth-generation agent, moxifloxacin, exhibits enhanced an equal affinity for topoisomerase II (DNA-Gyrase) and topoisomerase IV.

        • These enhancements make moxifloxacin potent against a broader range of pathogen while being less likely to be susceptible to mutant which exhibits they single resistance target to either one of the two topoisomerases.²²

        • Examples of fourth-generation fluoroquinolones include: clinafloxacin, moxifloxacin sitafloxacin, prulifloxacin, besifloxacin, delafloxacin.

          • To summarize then, fourth-generation quinolones  would be expected effective in managing:

            • (1) Nosocomial pneumonia,

            • (2) Intra-abdominal infections,

            • (3) Serious penicillin-or cephalosporin-resistant Streptococcus pneumoniae infections.²³

         

    • "Simplified antibiotic coverage diagram"

      Attribution Akinesia, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Antibiotics_coverage_diagram.jpg (December 10, 2017)

July, 2025