Quinolones are synthetic, bactericidal antibacterial agents with broad-spectrum activity. They inhibit the enzyme topoisomerase II, a DNA gyrase that is necessary for the replication of the microorganism.

1. Quinolones
As an antibacterial agent
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2. Quinolones
• The quinolones are a family
of synthetic bactericidal broad
spectrum drugs
• Derived from quinine.
• Figure shows the basic
fluoroquinolone molecule or
‘pharmacore’.
• The addition of a fluorine molecule at
position 6 was one of the earliest
changes to the structure.
• First gen. of Quinolones began with Nalidixic Acid (1962)
discovered by George Lesher & coworkers
• concentration-dependent bacterial killing.
•Zwitter Ionic in nature. Acidic (-COOH) group is common.
Quinolones

3. Journal of Antimicrobial Chemotherapy (2003) 51, Suppl. S1, 1–11 | DOI: 10.1093/jac/dkg212 | Development of the
quinolones | Monique I. Andersson and Alasdair P. MacGowan
Quinolones

4. Generation Drug Names Spectrum
1st
Cinoxacin
Nalidixic Acid
Oxolinic acid
Gram -ve but not
Pseudomonas
2nd
Addition of fluorine
Norfloxacin
Ciprofloxacin
Ofloxacin
Gram –ve (including
Pseudomonas)
some Gram+ (S. aureus)
3rd
Levofloxacin
Sparfloxacin
Moxifloxacin
Gemifloxacin
Same as 2nd generation:
extended Gram +ve
Coverage and expanded
activity against atypical
pathogens
4th
*Trovafloxacin
(removed from market in 1999)
Gatifloxacin
(Tequin removed from clinical use)
Same as 3rd generation:
broad anaerobic coverage
Generations of Quinolones
Quinolones

5. Development
of Quinolones
Quinolones

6. Spectrum of activity
Gram Positive
• Staphylococcus aureus
• Streptococcus
pneumoniae
• Some resistant
Streptococci
• Enterococcus sp
Gram Negetive
• E. coli
• Klebsiella sp
• Enterobacter sp
• Proteus sp
• Salmonella
• Shigella
• Serratia marcescens
• Neisseria sp
• Pseudomonas aeruginosaAtypical Bacteria
• Legionella pneumophila
• Chlamydia sp.
• Mycoplasma sp.
• Ureaplasma realyticum
BROAD SPECTRUM DRUG
Quinolones

7. Mechanism of action
• DNA gyrase (Topo II) is composed of two
pairs of subunits, 2GyrA and 2GyrB
• encoded by genes gyrA and gyrB,
respectively.
• It is responsible for introducing and
removing DNA supercoils and for
decatenating interlocked circular DNA.
• DNA gyrase safeguards against the
occurrence of replication induced
structural changes before advancement
of the replication fork.
Quinolones

8. • Topoisomerase IV In E. coli, it has two
ParC and two ParE subunits
• encoded by genes parC and parE genes.
• removal of DNA supercoils and
separation of newly built daughter DNA
after replication is complete.
• Topo II work before the replication fork
and topo IV works after the replication
fork on newly formed DNA
Quinolones
Mechanism of action

9. Quinolones block the reaction and trap gyrase or topoisomerase IV as a
drug-enzyme-DNA complex, with subsequent release of lethal, double-
stranded DNA breaks. These strands breaks leads to SOS response which
leads to DNA repair mechanisms involving low fidelity DNA pol. which
cause lethal mutations leading to genomic toxicity and finally cell death
Nature Reviews Microbiology 8, 423-435 (June 2010) | Michael A. Kohanski, Daniel J. Dwyer & James J. Collins
Mechanism of action
Quinolones

10. Therapeutic Uses
Diseases / infections Quinolone uses
Genito urinary Infections •Most commonly used
•UTI Caused by E.Coli
•Complicated UTI
•Norfloxacin , Levofloxacin, Ciprofloxacin
Prostatitis •Very effective, excellent penetration to
the tissue
•Levofloxacin is first line agent
•Ciprofloxacin in Gram –ve resistant
•Norfloxacin ,& Ofloxacin
Bacterial diarrheoas •Very effective against shigella,
salmonella, E.coli, Campylobacter jejuni
•Norfloxacin, ciprofloxacin , ofloxacin
STI •Effective against N. gonorrhoeae & C.
trachomatis
•Gatifloxacin and ofloxacin or sparfloxacin
•Pelvic inflammatory disease
Quinolones

11. Therapeutic Uses
• Skin and soft tissue infections (not involving S.
aureus) and also in diabetic foot infections
• Used widely in respiratory related infections.
Fluroquinolone Preferred Uses
Norloxacin UTI, Bacterial Diarrheoas
Ciprofloxacin UTI, Typhoid, Bacterial diarrheoas, Gonorrhea
Ofloxacin Tuberculosis, Leprosy, Atypical Pneumonia, Chlamydial
infections
Levofloxacin pnumonia, Bronchitis, UTI, Skin & soft tissue infections
Gatifloxacin Pnumonia, Bronchitis, UTI, Gonnococcal infections
Moxifloxacin Pnumonia, Bronchitis, Sinusitis, otitis media
Quinolones

12. Mechanisms of resistance
• Involves amino acid substitutions in a region of the GyrA or
ParC subunit termed the “quinolone-resistance–determining
region” (QRDR).
• This region occurs on the DNA-binding surface of the enzyme
• The QRDR in DNA gyrase is near tyrosine 122.
• Additional mutations in gyrA or mutations in gyrB or parC
augment resistance
• These substitutions decrease susceptibility by they reducing
drug affinity. Alternatively, mutations may marginally
• Also impair target enzyme function to an extent
TARGET-ENZYME RESISTANCE MECHANISMS
Quinolones

13. Mechanisms of resistance
• Gram-ve bacteria regulate membrane permeability by altering
expression of outer membrane porin proteins that form
channels for passive diffusion such as outer membrane proteins
OmpF and OmpC
• the Acr AB-TolC efflux pump plays a major role in quinolone
Mutations in acrR (a epressor of acrAB) increase pump activity.
• Mutations that inactivate marR (a repressor of marA) allow
MarA to activate acrAB, tolC, and a gene that decreases
translation of ompF, thus collectively decreasing influx and
increasing efflux of quinolones
EFFLUX RESISTANCE MECHANISMS
Quinolones

14. Mechanisms of resistance
• The plasmid-mediated quinolone resistance gene
was named “qnr.”
• Produce a 219- aa protein belonging to the
pentapeptide repeat family, which are involved in
protein-protein interactions
• Purified Qnr protein bind to and protect both
topo II & topo VI from inhibition by ciprofloxacin
• qnr has been acquired from some other source,
but it is not known where qnr originated
PLASMID-MEDIATED RESISTANCE
Quinolones

15. Mechanisms of resistance
DOI: 10.1039/C2MB25090J (Paper) Mol. BioSyst., 2012, 8, 2303-2311 | Hui Li et. Al.| Alterations of protein complexes
& pathways in genetic information flow & response to stimulus contribute to E. coli resistance to balofloxacin
Quinolones

16. Side effects
• Articular Damage:
– articular cartilage damage, and joint swelling
• Other adverse reactions:
– Tendon rupture (flourosis of tendons)
– Hypersensitivity
– Nausea, vomiting, diarrhea, Headache, dizziness,
other common antibiotic related side effects.
• Chemotherapy of quinolones in children and
newborns is still a debate (otitis media
resistance)
Quinolones

17. Future of Quinolones
• JNJ-Q2 -acute bacterial skin and skin-structure
infections & community- Acquired pneumonia
& against MRSA
• Delafloxacin (RX-3341) -against Gram-positive
bacteria such as MRSA. Anionic character
• Nemonoxacin -non-fluorinated Q. undergoing
clinical trials
• Development of Quinolones sensitive to DNA
related enzymes for cancer chemotherapy
Quinolones

18. Reference
• Monique I. Andersson and Alasdair P. MacGowan, Development of the
quinolones, Journal of Antimicrobial Chemotherapy (2003) 51, Suppl. S1,
1–11 DOI: 10.1093/jac/dkg212
• George A. Jacoby, Mechanisms of Resistance to Quinolones, Clinical
Infectious Diseases 2005; 41:S120–6 2005 by the Infectious Diseases
Society of America
• David T. Bearden, Larry H. Danziger, PharmD, Mechanism of Action of and
Resistance to Quinolones, www.medscape.com/viewarticle/418293_print
• Hui Li et. Al., DOI: 10.1039/C2MB25090J (Paper) Mol. BioSyst., 2012, 8,
2303-2311, Alterations of protein complexes and pathways in genetic
information flow and response to stimulus contribute to E. coli resistance
to balofloxacin
• Michael A. Kohanski, Daniel J. Dwyer & James J. Collins, Nature Reviews
Microbiology 8, 423-435 (June 2010)
Quinolones