Week 4 - Antibiotics: Inhibitors of Nucleic Acid Synthesis Flashcards
Rifamycins, Fidoxamicin-
inhibitors of RNA polymerase
Fluoroquinolones-
inhibitors of DNA replication
Sulfonamides, Trimethoprim-
Folate Antagonists
Metronidazole, Nitrofurantoin-
Indirect Inhibitor of DNA
Rifamycin - **Rifampin **(outside U.S. known as rifampicin)
Mechanism
Sprctrum
Resistance
Mechanism:
Bactericidal- Binds bacterial RNA polymerase at the active center, blocking the elongation of the mRNA
Spectrum: Gram + and -, Mycobacteria tuberculosis
Resistance:
Intrinsic resistance- in some bacterial strains the drug is unable to bind to the β subunit of RNA polymerase
Acquired resistance- the strain acquires mutations in rpoB gene preventing drug binding
Treat Mycobacteria tuberculosis with 4 antibiotics due to the high rate of resistance
What is tuberculosis treated with?
Rifampin
But treat with 4 (additional 3) antibiotics due to hight rate of resistance..
Rifampin Spectrum?
Gram + and -
mycobacteria tuberculosis
Adverse effects of Rifamycin - **Rifampin **
Adverse effects:
GI side effects, Hypersensitivity- Fever
Hepatotoxic-
Use caution when administering to patients with chronic liver disease
Induction of cytochrome P450 enzymes can induce the metabolism of other medicines leading to organ rejection and loss of seizure control. Seizure meds will be metabolized much quicker*
Turns body fluids orange-red and can stain contact lens
What increases Rifampin excrection in feces?
Deacetylation of Rifampin increases its excretion in the feces…
Liver damage will impair excretion*
Impairment of liver function leads to higher blood serum levels

Fidaxomicin
Mechanism
Spectrum
Resistance
Side effects
Mechanism: Bactericidal- Inhibits RNA polymerase by binding to sigma subunit of RNA polymerase
Spectrum: narrow spectrum sparing many of the gut flora, Gram positive anaerobes, C. difficile better at preventing recurrent infections
Resistance: Point mutation in RNA polymerase has been observed in vitro.. new drug so haven’t seen much resistence yet
Side effects:
Low absorption
Nausea, vomiting
Spectrum of Fidaxomicin
narrow spectrum sparing many of the gut flora, Gram positive anaerobes, C. difficile better at preventing recurrent infections
It is better than Vancomycin but not as good as fecal transplants*
Would you expect rifampin and ficaxomicin to exhibit cross resistance?
If you have been giving sombody rifampin and the bacteria become resistant.. if try to give fidaxomicin would the bacteria be resistant to fidaxomicin?
No. Drugs are binding to different areas of the enzymes.
What are the fluoroquinolones?
Ciprofloxacin, levofloxacin, moxifloxacin
Ciprofloxacin, levofloxacin, moxifloxacin
Mechanism
Spectrum
Resistance
Mechanism: Bactericidal- Inhibit DNA replication by binding bacterial DNA topoisomerase
Spectrum:
Broad spectrum- Gram+, Gram-, and atypical organisms like Mycoplasma
Resistance: Overprescribed
Active efflux of the drug
Mutations in topoisomerases
Ciproflaxacin, levofloxacin, moxifloxacin
Spectrum
Spectrum:
Broad spectrum- Gram+, Gram-, and atypical organisms like Mycoplasma
What antibiotics will work against atypical organisms like mycoplasmas?
The Fluoroquinolones:
Ciprofloxacin, levofloxacin, moxifloxacin
Mycoplasma have no….
Cell wall
What is the mechanism of fluoroquinolones?
Fluoroquinolones Ciprofloxacin, levofloxacin, moxifloxacin
Block bacterial DNA synthesis by binding to bacterial topoisomerase II (DNA gyrase) and topoisomerase IV.
Inhibition of topoisomerase II prevents relaxation of positively supercoiled DNA that is required for normal transcription and replication. Gram –
Inhibition of topoisomerase IV interferes with separation of replicated chromosomal DNA (decatenation) into the respective daughter cells during cell division.
Gram +

What do fluoroquinolones cause in double stranded DNA?
Fluoroquinolones cause double-stranded DNA breaks and cell death, which can be prevented through the activation of the DNA stress response (SOS) and DNA repair.

What are efflux transporters?
Multidrug Resistance occurs due to the upregulation of transporters capable of effluxing many types of drugs
This occurs in fluoroquinolones… ***
*Gram negative have 2 membrane layers…

If a strain of pseudomonas aeruginosa has become resistant to lefofloxacin which additional drugs do you expect the bacteria to be resistant to?
Nafcillin
Ciprofloaxin
Aztreonam
All
Cant determine
So… mechanism is to bind DNA topoisomerase inhibiting DNA…
So it could be ALL…
Main take away is that if bacterial become resistant to one drug, they will most likely be resistant to other drugs in the same class..

Adverse Effects of fluoroquinolones..
Adverse Effects:
GI side effects, confusion and photosensitivity
Tendon Rupture
Contraindicated in pregnant women
Prolongation of the QT interval
Important facts on fluoroquinolones
Important Facts:
Chelate cations so don’t take with calcium, iron, aluminum, and zinc
avoid dairy products or calcium-fortified juice
Adjust for renal dysfunction for all agents except moxifloxacin, which is not excreted into the urine
Avoid antacids…
What can ciprofoxacin be used for in terms of biologica warfare?
From PubMedHeath…
In the event of biological warfare, ciprofloxacin may be used to treat and prevent dangerous illnesses that are deliberately spread such as plague, tularemia, and anthrax of the skin or mouth. Talk to your doctor about the risks of using this medication for your condition






