Gyrase inhibition

Gyrase inhibition by Quinolone and fluroquinolones antibiotics with pictorial represenations

1. GYRASE INHIBITION Presented by, Raghavendra Prabu K S M.Tech I Year Biopharmaceutical Technology

2. Topics covered Introduction 3 D Structure Inhibitors (Drugs) Classification of drugs Mechanism of action Derivatives References

3. Gyrase: DNA gyrase is an essential bacterial enzyme that catalyzes the ATP-dependent negative super-coiling of double-stranded closed-circular DNA It belongs to the class Topoisomerase Topoisomerases  are isomerase enzymes that act on the topology of DNA.

4. Bacterial  DNA gyrase is the target of many  antibiotics , including  nalidixic acid ,  novobiocin , and ciprofloxacin . Here the Inhibitors such as Quinolones mainly against Gram negative bacteria Due to their action on DNA gyrase While action on Topoisomerase IV on Gram positive bacteria

5. Structure of DNA GYRASE enzyme in Eukaryote

6. Gyrase Structure

7. Inhibitors ~2 main classification Quinolones ,particularly fluroquinolones with their broad antimicrobial activity are used in disease causing oraganisms . Fluroquinolones are the drugs that are chemically related to nalidixic acid and has fluorine in their chemical structure.

8. Quinolones The  quinolones  are a family of synthetic broad-spectrum antibiotic drugs.  Quinolones, and derivatives, have also been isolated from natural sources (such as plants, animals and bacteria) and can act as natural antimicrobials and/or signalling molecules.

9. Quinolones inhibits DNA gyrase ~ topoisomerase II DNA topoisomerase IV

10. Nalidixic Acid 4-quinolone derivaive Effective against G- ve bacteria __ E.coli , shigella , many strains of proteus Relatively ineffective against G+ve bacteria due to development of resistance Readily absorbed in GI tract Serum level of the drug usually low 80 % eliminated thru, urine span of 8hrs 20% active and inactive forms in the urine

11. Fluroquinolones The fluorine in the chemical structure called fluoroquinolones Chemically related to nalidixic acid This fluorine increases the activity of spectrum Highly effective orally Bactericidal with broad spec

12. Effective against bacteria which are resistant to beta lactum and aminoglycoside They are also safe to use

13. Fluroquinolones Generations Generation Name Oral bioavl . T half Indications 2 Class I Norfloxacin 30 – 40 % 3- 4 hrs UTI, Prostatitis Lomefloxacin 90 % 6 – 8 hrs 2 Class II Ofloxacin Ciprofloxacin 60-70 95 3. 3 to 4.9 5 to 7 UTI, Typhoid, Gonorrhea, Gastroentiritis , skin , soft tisue infections Pefloxacin 90 8-13 3 rd Gen Levofloxacin Sparfloxacin Gemifloxacin >90 70 6-8 Preferred in community acquired Pneumonia Moxifloxacin 90 7

14. These Fluroquinolones also effective against Legionella , brucell , chlamydia and mycoplasma pneumoniea Mycobacterium tuberclosis and M.avium complex Quinolones such as ciprofloxacin are potent liver enzyme inhibitors and can reduce the metabolism of warfarin , theophilline and sulfonylurease

15. Therapeutic uses Quinolones.. Urinary tract infections, even when caused by multifrug -resistant bacteria, intestinal and biliary tract infections, soft tissue infections, Respiratory tract infections.

16. A/E Adverse effects include… GI Toxicity : nausea, diarrhoea CNS Toxicity: dizziness, headache mildly, Tendon and cartilage damage : rupture of shoulder, hand, achilles tendons

17. References :- https:// www.ncbi.nlm.nih.gov/pubmed/1657531 Wikipedia for structure Pharmacology and Pharmacotherapeutics book R.S.Satoskar 24 th edition