DNA Gyrase Inhibitors -Quinolones,Fluoroquinolones ,its Structure,Antimicrobial activity ,Mechanism of action,classifications ,Mechanisms of Resistance,Pharmacokinetics,Clinical uses,Adverse effects

1. DNA Gyrase Inhibitors
Quinolones
Fluoroquinolones
Presented By
Mr.Vijay Salvekar
Dept. of Pharmacology
GRY Institute of Pharmacy

2. Quinolones
Bactericidal :Broad Spectrum Antibiotics
Increasingly Used - Safety-availability -Orally ,
Parenterally –Favorable P’kinetics
Relatively Few Side Effects;
Microbial Resistance To Their Action Does Not
Develop Rapidly.

3. Quinolone Structure
Pyridone ring*
*Required for antibacterial activity

4. Antimicrobial activity
Bactericidal
Excellent Activity Against Aerobic Gram{- }
Several Newer Agents -- Improve Activity Against
Aerobic Gram{+} Bacteria.
 They Also Are Effective Against -Chlamydia Spp.,
Legionella Pneumophila, Anaerobic Bacteria,
Mycobacteria
Some Agents Have Limited Activity Against Multiple
Resistance Strains.

5. Mechanism of action
Topoisomerases :
Enzymes that control and modify the topological States of
DNA in cells.
• Topoisomerase I,III catalyse merely the relaxation
DNA
• Topoisomerase II
（DNA gyrase ）catalyse the supercoiling of DNA
• Topoisomerase IV
involved in the separation process of the
DNA daughter chains after chromosome duplication.
The quinolone antibiotics target bacterial
DNA gyrase (gram-negative bacteria)
Topoisomerase IV (gram- positive bacteria).

6. Mechanism of action
Inhibition of DNA gyrase →
prevents the relaxation of positively supercoiled DNA that
is required for normal transcription and replication
Inhibition of topoisomerase IV →
interferes with separation of replicated chromosomal DNA into the
respective daughter cells during cell division.

7. Roughly be classified into 4 generations
First generation– Nalidixic Acid
Second generation-Pipemidic Acid
Third generation(fluoroquinolones,FQs)
– Norfloxacin, Ciprofloxacin, Ofloxacin,
Enoxacin.
Fourth generation– Lomefloxacin

9. Novel Group of Synthetic Antibiotics Developed
In Response to Growing Resistance
Agents Available Today Are All Structural
Derivatives of Nalidixic Acid
The Fluorinated Quinolones (Fqs) Represent A
Major Therapeutic Advance:
Broad Spectrum Of Activity
Improved PK Properties – Excellent Bioavailability,
Tissue Penetration, Prolonged Half-lives
Overall Safety
 Disadvantages: Resistance, Expensive
FLUOROQUINOLONES

10. Inhibiting bacterial-- topoisomerase (DNA gyrase)
topoisomerase IV,
Block bacterial DNA synthesis and put bacteria to
death.
Inhibition of DNA gyrase prevents the relaxation
of positively supercoiled DNA that is required for
normal transcription and replication.
Inhibition of topoisomerase IV probably interferes
with separation of replicated chromosomal DNA
Into the respective daughter cells during cell
division
Mechanisms of Action

11. Classification
(1st group) :Norfloxacin
Least active against gram (-) and gram (+)
Derived from nalidixic acid
Common pathogens that cause UTI

12. (2nd group): Ciprofloxacin, Levofloxacin,
Ofloxacin, Enoxacin,lomefloxacin And
Pefloxacin
Excellent activity against gram (-) cocci and
bacilli:S. aureus (systemic infecitons)
Greater activity against gram (+)
S. pneumoniae– Staphylococci

13. (3rd group):
Gatifloxacin, gemifloxcin and moxifloxacin
Improved activity against gram (+)
S. pneumoniae
Some staphylococci
Enhanced activity against anaerobes

14. In the past ten years there has been a
dramatic increase in the frequency of
resistance to quinolones
 Selective antibiotic pressure and horizontal
spread of strains appears to be responsible.
Use of quinolones in animal feed has also
contributed to increasing resistance among
some bacterial species
Mechanisms of Resistance

15. Resistance can emerge during therapy -
especially with S. aureus
 A single mutation is sufficient to cause
resistance.
Resistance is chromosomal rather than
plasmid-mediated.
 Mutations occur in the genes for DNA
gyrase(topoisomerase type II)

16. Mutations also occur in the genes for
topoisomerase IV
•Appear to be primary site for S.pneumoniae
and other Gram positives
 Active efflux system
• Present in both Gram positive and negative
bacteria

17. Altered target sites – chromosomal mutations in
genes that code for DNA gyrase or topoisomerase
IV
most important and most common
Altered cell wall permeability – decreased porin
expression
Expression of active efflux – transfers FQs out of
cell

18. Pharmacokinetics
Good oral bioavailability (80-95%).
Ofloxacin, enoxacin and lomefloxacin are almost
completely absorbed orally;
 norfloxacin is 35-45%; ciprofloxacin is 67%
orally absorbed.
The FQs are widely distributed in body fluids and
tissue.

19. The concentrations in prostate, kidney, neutrophils and
macrophages exceed serum concentrations, but in the
cerebrospinal fluid are low.
Serum half-lives range from 3 to 10 hours
 Elimination through the kidneys
therefore the dosage must be adjusted according to renal
function.
Eliminated partly by hepatic metabolism and biliary
excretion
Dosage reduction needed in renal dysfunction

20. Clinical uses
Urinary tract infections: FQs are effective
for uncomplicated and complicated urinary tract
infections even when caused by multidrug-resistant
bacteria.
Ciprofloxacin and ofloxacin are effective for
gonococcal infection;
Ofloxacin is effective for chlamydial urethritis or
cervicitis.

21. 2. Intestinal tract infections:
intra-abdominal infections and bacterial
diarrhea caused by shigella, salmonella E.
Coli, or campylobacter.
3. Prostatitis

22. 4. Respiratory tract infections:
 Not been routinely recommended for treatment of
pneumonia and other upper respiratory tract infections.
These infections, predominantly caused by pneumococci
and streptococci, are usually well treated with betalactams
or macrolides.
However, levofloxacin, sparfloxacin, and newer FQs
with enhanced G+ activity and activity against atypical
pneumonia pathogens (e.g. chlamydia, mycoplasma, and
legionella) are likely to be effective and used increasingly
for treatment of upper and lower respiratory tract
infections

23. 5. Infections of the bones, joints, skin and soft
tissues:
Including those caused by multidrug-resistant
organisms such as pseudomonas and
enterobacter.
6. Others:
Ciprofloxacin or ofloxacin is occasionally used
for treatment of tuberculosis and atypical
mycobacterial infections.

24. Current Uses of Fluoroquinolones
Ciprofloxacin: wide range of infections pneumonias, bone
infections, diarrhea, skin infections and urinary tract
infections. Not good for methicillin resistant
Staphylococcus aureus
Norfloxacin: better for UTI
effective against Gram-negative (including Pseudomonas
aeruginosa) and Gram-positive UTIs and prostatitis, but
not in systemic infections

25. • Levofloxacin:
• Community-acquired pneumonia
• Atypical pneumonia (M. pneumoniae)
• Moxifloxacin – overcomes the problems with S.
pneumoniae
• Acute bacterial sinusitis; mild to moderate
community-acquired pneumonia

26. Adverse effects
Gastrointestinal upsets (the most
common):Nausea, vomiting, diarrhea;
Allergy and anaphylaxis
Central Nervous System (1~7%):
Headache, agitation, insomnia, dizziness,
hallucinations and seizures (rarely)

27. Thank you