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.

9. 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.

10.  Quinolones inhibits
(a) DNA gyrase ~topoisomerase II
(b) DNA topoisomerase IV

11. 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

12. 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

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

14. 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
3rd Gen Levofloxacin
Sparfloxacin
Gemifloxacin
>90
70
6-8 Preferred in
community
acquired
Pneumonia
Moxifloxacin 90 7

16.  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

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

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

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