Quinolone Antimicrobial Agents Flashcards
Name the four quinolone core structures
Quinolone
Cinnolone
1,8-Naphthyridone
Pyridopyrimidone
First generation quinolones are used to treat
Gram Negative Bacteria
Only useful for lower urinary tract infections
Two examples of first generation quinolones?
Oxolinic acid
Nalidixic acid
Defining characteristics of second generation quinolones
Fluorine substituent at C6
Heterocyclic ring at C7
Three common examples of second generation quinolones
Norfloxacin
Ciprofloxacin
Levofloxcin
Second generation quinolones are much more effective against…
G- species (including Pseudomonas)
Extended activity against G+ organisms and mycoplasma
The most potent flouroquinolone
Ciprofloxacin
How are 3rd and 4th generation quinolones different from 2nd?
Multiple Fluorine atoms
3rd/4th Generation quinolones are more effective against…
G+ organisms (esp. strep pneumo)
None as good as Cipro against Gram negatives
Two examples of 3/4th generation quinolones
Sparfloxacin
Moxifloxacin
Moxifloxacin is considered a drug…
of last resort
Severe Side Effects
How do DNA topoisomerases and gyrases cleave DNA?
A Nucleophilic attack on a phosphodiester linkage
One strand becomes free, the other enzyme linked
The nucleophile targeted by DNA topiosomerases and gyrases?
the phenolic hydroxyl group of a tyrosine residue
Decribe the method of DNA transport by bacterial topoisomerases and gyrases?
- G-segment DNA binds a high affinity CAP region site
- CAP regions remain in closed conformation
- 2 ATP bind ATPase domains
- N gate closure with T seg trapped in the DNA capture domain
- G-sgement DNA gate opens, T seg passes through
- G-segment DNA religates. C-gate opens
G-segment binding requires what enzyme conformation
An open N gate and an opening between the two B regions of the protein
Once bound, the CAP regions remain closed
What is likely assoiciated with ATP hydrolysis of topiosomerases? Why?
A conformational change
To help squeeze the T segment through the open gate
How is the cycle of Topisomerase activity ended?
Rapid closure of the C gate
Release of hydrolysis products and open N gate
The dimeric enzyme binds _____ and cleaves the strands with ______
duplex DNA
A Four Base Stagger
Clevage involves covalent attachment of…
Each subunit of the dimer through a phosphotyrosine linkage to the 5’ end of the DNA
When would the gyrase/topisomerase mechanism be used within the same molecule? From different ones?
Same – Relaxation, Knotting, Unknotting
Different – Catenation, Decatenation
Requirements for topisomerase/gyrases to be active?
Mg++
ATP hydrolysis
How is the phosphodiester backbone rejoined/ligated?
Nucleophliic Displacement of the Protein Tyrosine residue
Quinolone antibiotics bind to…
the Cleavage complex that exists after a strand is broken
What happens after the quinolone antibiotic has bound?
The clevage comlex is stabilized and the religation reaction is inhibited. This blocks progression of the replication fork and the DS breaks will lead to apoptosis.
Most common therapeutic uses of quinolones?
Which ones?
UTIs
Norfloxacin, Ciprofloxacin, ofloxacin, and nalidixic acid
Treatment for prostatitis?
Norfloxacin, Ciprofloxacin, Ofloxacin
STDS treatable with quinolones?
Neisseria gonorrhoeae
Chlamydia
Ducreyi
Treatments for gonorrhea and ducreyi?
Ciprofloxacin
Treatments for Chlamydia?
Ofloxacin
Sparfloxacin
First line treatment against gonorrhea
Ceftriaxone
Too much resistance to quinolones
Quinolones can be used to treat what GI illness?
Which drugs?
Traveler’s Diarrhea, Reduces time for cholera
Norfloxacin, Ciprofloxacin, Ofloxacin
Quinolones effective against Strep pneumo
Moxifloxacin
______ as a sole therapy is effective in 50% of diabetic foot infections
Ciprofloxacin
______ and ______ are effective against intracellular bacteria
Norfloxacin
Ciprofloxacin
Fluoroquinolone resistance mechanisms include…
Decreased cellular permeability
Efflux Pumps
Mutation of the target enzymes
Two specific types of mutations that might alter quinolone efficacy
- Mutation of a-subunit of DNA gyrase that inhibits binding affinity for the drug
- B-subunit mutations
Especially if these mutations are additive
Floroquinolone penetration of G- bacteria depends on…
diffusion through porin channels
Bioavailability of fluoroquinolones?
Readily absorbed orally
high bioavailability
Which flurorquiolone isn’t dependent on renal and hepatic clearance?
Oxafloxacin (almost entirely renal)
Quinolones should not be distributed with foods/drugs containing…
heavy metals
They form insoluble chelates
The major inactive metabolite of quinolones
the glucuronide at the 3 carboxyl position
Most common side effects of quinolones?
Nausea, Vomiting, and Diarrhea
CNS reactions associated with quinolones?
Headache and Dizziness
Hallucinations, Delirium, Seizures
Why don’t you give quinolones to patients under 18?
Exception?
Damage to growing cartilage, arthropathy
Exception - CF patients
Photosensitivity has been reported with…
Lomefloxacin
Uncontrolled sugar in diabetic patients is associated with…
Gatifloxacin
