LEC 35 Antimicrobials III Flashcards
What are the 3 antibiotic targets inside the cell?
generally speaking
- Ribosome
- Metabolic Enzymes
- DNA
What are the two subunits of the prokaryotic ribosome?
- 30S
- 50S
Together they form a 70S Ribosome
What are the subunits of the eukaryotic ribosome?
- 60S
- 40S
Together, they make an 80S ribosome
How do tetracyclines work?
- Reversibly bind 30S subunit preventing formation of the initiation complex
- Bacteriostatic
What are some examples of tetracyclines?
- Tetracycline
- Minocycline
- Doxycycline
What is the spectrum of tetracyclines?
Broad-spectrum including
* Mycoplasma pneumoniae (no cell wall)
* Rickettsia, Chlamydia (intracellular pathogens)
* Borrelia (Lyme disease)
What is the number one reason for tetracycline resistance?
- Acquisition of tet transport genes which allow the bacteria to form the drug efflux pump
- Doesn’t matter if the drug gets in the cell, bc it is pumped right back out
Which tetracycline is less subject to export by the drug efflux pump?
Minocycline
What is the new semisynthetic glycylcycline and why was it developed?
What’s its MOA?
- Tigecycline (Tygacil)
- Developed to overcome efflux pumps
- Blocks tRNA binding necessary for protein synthesis
- Also Broad Spectrum like other tetracyclines
Binds 30S subunit more efficiently than other tetracyclines
How do aminoglycosides work?
- Bind the 30S subunit
- Some are bactericidal and some are bacteriostatic
What are some of the bactericidal aminoglycosides?
- Streptomycin
- Kanamycin
- Neomycin
- Amikacin
- Gentamicin
- Tobramycin
Notice the -mycin/micin endings
Which two antibiotics end in -mycin but are NOT aminoglycosides?
- Erythromycin
- Vancomycin
Which aminoglycoside is bacteriostatic?
Spectinomycin
What is the main way that resistance to aminoglycosides happens?
- Acquired resistance: modification of the abx
- Transferases (acetyl, adenyl, phospho)
- Effect is abx dependent (a modification that inactivates one aminoglycoside may have no effect on another aminoglycoside)
How does chloramphenicol work?
- Binds 50S subunit and prevents elongation of the peptide chain
Mostly topical use d/t toxicity (eye drops)
How does resistance to chloramphenicol occur?
- Modification of antibiotic
- contains a gene (CAT) for chloramphenicol acetyltransferase
- acetylates abx preventing it from binding the subunit
What 3 groups are included in MLS Abx?
- Macrolides
- Lincosamides
- Streptogramin
How do the MLS abx work?
Bind the 50S subunit of the intact ribosome and inhibit translocation of the ribosome along the RNA
What are some examples of macrolides?
- Erythromycin
- Azithromycin (z-pack)
- Clarithromycin
What is an example of a lincosamide?
Clindamycin
What is are some examples of streptogramins?
Quinupristin + Dalfopristin = streptogramin A & B = Synercid
All same drugs, just different names and a combo drug
How does resistance to MLS abx occur?
- Modification of 50S subunit target NOT the abx - methylation of 23S rRNA
- acquisition of gene, erm. (erythromycin resistance methylase)
- causes reduced affinity for the abx
How do oxazolidinones (Zyvox/linezolid) work?
- Binds 50S subunit and inhibits formation of 70S initiation complex
- Inhibits formation of 1st peptide bond
- Bacteriostatic
Resistance: modification of 23S rRNA
Why is tedizolid better than linezolid?
- 4-6 times more potent against staphylococci and enterococci
- active against linezolid resistant staphylococci
Why are the oxazolidinones important?
Both linezolid and tedizolid have at least some activity against VISA and VRSA
What enzyme controls DNA supercoiling?
DNA gyrase
along with other topoisomerases
Why is DNA gyrase an effective drug target?
- All cells have DNA gyrase, but bacterial DNA gyrase is more sensitive
- Abx bind at concentrations lower than that required to damage mammalian topoisomerases
What are some examples of fluorquinolones?
- norfloxacin
- ciprofloxacin
- levofloxacin
- gatifloxacin
Why are quinolones (nalidixic acid) not used anymore?
widespread resistance
How do fluoroquinolones work?
DNA gyrases inhibitors
What is the spectrum of fluoroquinolones?
- Broad-spectrum including mycobacterium
- Effective against intracellular pathogens (concentrated inside phagocytic cells)
- Norfloxacin is concentrated in urine making it good for UTIs
How does Rifampin work?
- binds beta subunit of DNA-dependent RNA polymerase and prevents binding to the promoter
- Does NOT impair mammalian RNA polymerase
What’s the spectrum of Rifampin?
- Gram-positive and Mycobacterium
- Cornerstone drug for TB
Why are gram-negatives intrinsically resistant to Rifampin?
hydrophobic drug cannot cross outer membrane
How does acquired resistance to Rifampin occur?
- a single step mutation in the gene encoding the beta subunit of RNA polymerase
- Rifampin RARELY USED ALONE (if ever)
Why is tetrahydrofolate production a good drug target?
- Mammalian cells get THF from the diet but bacteria have to make it
- Required for biosynthesis of amino acids and nucleic acids
How do sulfonamides work?
- competitive inhibition of dihydropteroate (DHPS)
- partial shutdown of THF synthesis (bacteriostatic)
How does Trimethoprim work?
- competitive inhibition of dihydrofolate reductase (DHFR)
- partial shutdown of THF synthesis
Why are sulfonamides and trimethoprim always used together?
They effectively shut down THF synthesis making them bactericidal when used together
