GYRASE INHIBITION

Presented by,Raghavendra Prabu K S

M.Tech I Year Biopharmaceutical Technology

Topics covered Introduction3 D StructureInhibitors (Drugs)Classification of drugs Mechanism of action DerivativesReferences

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.

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

Structure of DNA GYRASE enzyme in Eukaryote

Gyrase Structure

Inhibitors ~2 main classificationQuinolones ,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.

QuinolonesThe 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.

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

Nalidixic Acid 4-quinolone derivaiveEffective against G-ve bacteria __ E.coli ,

shigella , many strains of proteusRelatively ineffective against G+ve

bacteria due to development of resistanceReadily absorbed in GI tractSerum level of the drug usually low80 % eliminated thru, urine span of 8hrs20% active and inactive forms in the urine

Fluroquinolones The fluorine in the chemical

structure called fluoroquinolones Chemically related to nalidixic acid

This fluorine increases the activity of spectrum

Highly effective orallyBactericidal with broad spec

Effective against bacteria which are resistant to beta lactum and aminoglycoside

They are also safe to use

Fluroquinolones Generations

Generation Name Oral bioavl. T half Indications2 Class I Norfloxacin 30 – 40 % 3- 4 hrs UTI,

ProstatitisLomefloxacin 90 % 6 – 8 hrs

2 Class II OfloxacinCiprofloxacin

60-7095

3. 3 to 4.95 to 7

UTI, Typhoid,Gonorrhea,Gastroentiritis, skin ,soft tisue infections

Pefloxacin 90 8-133rd Gen Levofloxacin

SparfloxacinGemifloxacin

>90

70

6-8 Preferred in community acquired Pneumonia

Moxifloxacin 90 7

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

Therapeutic usesQuinolones..Urinary tract infections, even when

caused

by multifrug-resistant bacteria, intestinal and

biliary tract infections, soft tissue infections,

Respiratory tract infections.

A/EAdverse effects include…GI Toxicity : nausea, diarrhoea

CNS Toxicity: dizziness, headache mildly,

Tendon and cartilage damage : rupture of shoulder, hand, achilles tendons

References :-https://

www.ncbi.nlm.nih.gov/pubmed/1657531

Wikipedia for structurePharmacology and

Pharmacotherapeutics book R.S.Satoskar 24th edition