Antibacterial Action Mechanism of Fluoroquinolones.pptx

Antibacterial Action Mechanism of Fluoroquinolones.pptx

1. Presentation on Anti-bacterial Action Mechanism of Fluoroquinolones & Resistance Mechanism Submitted by- Samad Muhammad Abdus ID-AM202318003 School of Medicine Jeju National University For- Kang Hee-Kyung Professor School of Medicine Jeju National University

2. Fluoroquinolones: Fluoroquinolones are an important class of wide-spectrum synthetic antibacterial agents, which kill bacteria and fight infections. The term quinolone refers to potent synthetic chemtherapeutic antibacterial agent. Fluoroquinolones contain a fluorine atom in their chemical structure and are effective against both Gram-negative and Gram-positive bacteria. They are important for treating certain bacterial infections, some of which may be serious or life-threatening. This group of antibiotics includes few generation, the examples are given below- 1st Generation: Nalidixic acid, Oxolinic acid, Cinoxacin, Piromidic acid, etc. 2nd Generation: Ciprofloxacin, Lomefloxacin, Norfloxacin, Ofloxacin, etc. 3rd Generation: Levofloxacin, Sparfloxacin, Temafloxacin etc. 4th Generation: Gatifloxacin, Gemifloxacin, Moxifloxacin, etc.

3. Antibacterial action mechanism of Fluoroquinolones: The fluoroquinolones are the only direct inhibitors of DNA synthesis; by binding to the enzyme-DNA complex, they stabilize DNA strand breaks created by DNA gyrase and topoisomerase IV. Ternary complexes of drug, enzyme, and DNA block progress of the replication fork. Quinolones are chemotherapeutic bactericidal drugs. They interfere with DNA replication by preventing bacterial DNA from unwinding and duplicating. 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. Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA into the respective daughter cells during cell division. While all quinolones have activity at both target sites, most have higher affinity for one or the other. This can explain differences in spectra of activity since DNA gyrase is the primary target for gram-negative and topoisomerase IV is the primary target for gram-positive organisms. Whether, Defloxacin has a uniquely balanced affinity for both target sites, which may contribute to its broader spectrum of activity and reduced likelihood for induction of resistance.

4. Antibacterial action mechanism of Fluoroquinolones (continued):

5. Antibacterial action mechanism of Fluoroquinolones (continued): Quinolones interact with both DNA gyrase, the drug's primary target, and topoisomerase IV, a similar type II topoisomerase, in order to exert their effects. These 2 enzymes frequently have different quinolone sensitivity ranges within a single bacterium; typically, DNA gyrase is more sensitive in Gram-negative bacteria while topoisomerase IV is more sensitive in Gram-positive bacteria. Genetic testing often identify the more sensitive enzyme as the main medication target, although there are reported, poorly understood outliers. Quinolone binding appears to cause modifications in both DNA and the topoisomerase that take place independently from the DNA cleavage that is the hallmark of quinolone action, leading to the development of the ternary complex of DNA, DNA gyrase, and either topoisomerase IV or DNA gyrase. X-ray crystallographic analyses of a gyrase fragment A component has shown regions that are likely to be quinolone binding sites, as has yeast topoisomerase IV, which has similarity to the subunits of both DNA gyrase and topoisomerase IV. Nevertheless, to yet, no topoisomerase crystal structures with DNA and quinolone have been published.

6. Resistance mechanism of Fluoroquinolones: To counteract the effect of quinolones, bacteria have developed various resistance mechanisms to these antibiotics. Bacterial resistance to quinolones is mainly based on three points: 1. Chromosomal mutations in coding genes (mutations that alter the objectives of the drug). 2. Mutations associated with the reduction of the intracytoplasmic concentration of quinolones. 3. Producing an Efflux Pump

7. Resistance mechanism of Fluoroquinolones (continued): Resistance to fluoroquinolones mostly occurs by two mechanisms that are mutations in the both target enzymes DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria. The second way that reduced accumulation of the fluoroquinolones can occur is through an efflux system. Resistance is due to increased expression of chromosomal gene leading to increased efflux of the fluoroquinolones

8. Altered target: Mutations in the bacterial DNA gyrase and Topoisomerase IV have developed a decreased affinity for fluoroquinolones. Resistance is frequently associated with mutations in both gyrase and topoisomerase IV. Decreased accumulation: Reduced intracellular concentration of the drugs in the bacterial cell is linked to two mechanisms. One mechanism is associated with an energy-dependent efflux system in the cell membrane. The other mechanism involves a decreased number of porins in the outer membrane of the resistant cell, thereby impairing access of the drugs to the intracellular topoisomerases. Resistance mechanism of Fluoroquinolones (continued):

9. References: 1.https://pubmed.ncbi.nlm.nih.gov/11249823/#:~:text=The%20fluoroquinolones%20are%20the%20only,progress%20of%20the%20replication%20fork. 2. https://www.hey.nhs.uk/patient-leaflet/fluoroquinolone-antibiotics-ciprofloxacin-moxifloxacin-levofloxacin-ofloxacin-what-you-need-to-know/ 3.https://www.microbiologyresearch.org/docserver/fulltext/jmm/66/5/551_jmm000475.pdf?expires=1679124578&id=id&accname=guest&checksum=A15A934FCC8974C4B632A4707A00F64A 4. https://www.intechopen.com/chapters/72711 5. https://aujmsr.com/fluoroquinolone-antibiotics-an-overview/