quinolones | drug develoupment | mechanism of action | future
TRANSCRIPT
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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