QuinolonesAs an antibacterial agent

Arun.V.2nd sem

M.Sc. BMB,14368005

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.

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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. MacGowanQ

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Generation Drug Names Spectrum

1stCinoxacin

Nalidixic AcidOxolinic acid

Gram -ve but not Pseudomonas

2nd

Addition of fluorine

NorfloxacinCiprofloxacin

Ofloxacin

Gram –ve (including Pseudomonas)

some Gram+ (S. aureus)

3rdLevofloxacin Sparfloxacin MoxifloxacinGemifloxacin

Same as 2nd generation: extended Gram +ve

Coverage and expandedactivity 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 QuinolonesQ

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Development of Quinolones

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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

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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.

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• 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

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Mechanism of action

Quinolones block the reaction and trap gyrase or topoisomerase IV as adrug-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 actionQ

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Therapeutic UsesDiseases / 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

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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 mediaQui

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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

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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

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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

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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 balofloxacinQ

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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)

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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

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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)

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