2.2.2. Antibiotics II Flashcards
Eukaryotic vesus Prokaryotic Ribosomes
Eukaryotic: 60S + 40S = 80S
Prokaryotic: 50S + 30S = 70S
*Structural differences are one basis for selective toxicity
Mitochondria and Selective Toxicity
Mitochondria have their own DNA and their own ribosomes (ribosomes are more similar to bacterial ribosomes than to eukaryotic ones). Therefore, if antibiotic diffuses across all membranes this can be a problem
Components of the 30S ribosomal subunit
- one rRNA molecule (16S)
- 21 different proteins (S1-S21)
Components of the 50S ribosomal subunit
- two rRNA molecules (5S and 23S)
- 31 different proteins (L1-L31)
3 Basic Steps of Protein Synthesis
- Amino acid activation
- Formations of Initiation complexes (30S and 70S)
- Polypeptide Chain Synthesis
Amino acid activation
aka “Charging” of tRNA by the enzyme aminoacyl-tRNA synthetase
Formation of Initiate Complexes
Step 1: charged tRNA, mRNA and 30S ribosomal subunit (includes IFs and GTP) bind
Step 2: the 50S binds and creates the 70S complex
4 Steps of Polypeptide Chain Synthesis
- Recognition
- Peptidyl Transfer
- Translocation
- Release
Antibiotics that target amino acid activation
NONE, unable to achieve selective toxicity
Antibiotics that target the initiation complexes
Oxazolidinones prevent the formation of the 70S ribosomal ternary complex by binding to the 50S ribosomal subunit
Linezolid (Zyvox)
The first of a new class of antibiotics called oxazolidinones (binds to 50S), used to treat Gram-positive infections
Is linezolid bacteriostatic or bactericidal?
BOTH: it is bacteriostatic for staphylococci and enterococci, but is is bactericidal for streptococci (strong/irreversible interaction b/w drug and 50S = bactericidal)
Antibiotics that are inhibitors of recognition
Aminoglycosides: prevent codon, anti-codon recognition
Aminoglycosides
Targets specific proteins in the 30S ribosomal subunit: Streptomycin, Kanamycin, Tobramycin, Gentamicin, Neomycin, Amikacin, Paramomycin, etc.
3 Mechanisms of Streptomycin
- Misreading
- Cyclic Polysomal Blockade
- Faulty Outer Membrane Proteins
Misreading (streptomycin)
A-site becomes distorted (leads to inactive ribosomes or incorrect amino acid insertion)
Cyclic Polysomal Blockade (streptomycin)
Although the 70S complex forms, it is unstable and falls apart b/c streptomycin is bound to 30S
Faulty Outer Membrane Proteins (streptomycin)
Translational misreading leads to mutant outer membrane proteins that make the bacterial membrane leaky (more drug leaks into the cell and acts at the 30S complex)
Benefits of Aminoglycoside therapy
- Rapid bactericidal effect
- Broad spectrum
- Effective against Pseudomonas
Drawbacks of Aminoglycoside therapy
- Resistance
- Ototoxicity and nephrotoxicity
- Antagonized by anaerobiasis, low pH, and ions
- Ineffective against most intracellular bacteria
- Induce bacterial biofilm formation
Ways to develop resistance to Aminoglycosides
- Altered target in 30S ribosomal subunit
- Decreased uptake into the cell
- Enzymatic modifications of the aminoglycoside (transposons or plasmids)
Aminocyclitol
Inhibits recognition (e.g., spectinomycin)
Spectinomycin
- Inhibits recognition
- Bacteriostatic
- Causes the formation of unstable 70S initiation complexes (BUT DOES NOT CAUSE MISREADING AND DOES NOT INHIBIT POLYSOMAL RIBOSOMES)
What does spectinomycin treat?
Exclusively for the treatment of gonorrhea caused by B-lactamase-producing gonococci or to treat gonorrhea in patients allergic to penicillins
Tetracyclines
- Inhibitors or recognition
- Broad spectrum
- Bacteriostatic
- Bind to the 30S ribosomal subunit and inhibit binding of aa-tRNA to the A site
What does tetracycline treat?
Chlamydia, Mycoplasma, Rickettsia (i.e., intracellular pathogens)
Resistance to Tetracyclines
- Decreased uptake (mutations in the OmpF porin)
- Efflux from the bacterial cell
- Elongation factor-like proteins that protect the 30S ribosomal subunit
Chloramphenicol
- inhibitors of peptidyl transfer
- broad spectrum and bacteriostatic
- binds reversible to the 50S ribosomal subunit and alters the tRNA structure blocking peptidyl transfer
Lincomycin and Clindamycin
- inhibitors of peptidyl transfer
- same action as chloramphenicol
- very effective for treatment of G+ bacterial infections
What does Clindamycin treat?
staphylococcal and anaerobic G- bacterial infections
Resistance to chloramphenicol
plasmid-encoded acetyltransferase that catalyze the acetylation of -OH groups, which prevents 50S binding
Resistance to clindamycin
Methylation of 23S ribosomal RNA which prevents drug binding to the 50S ribosomal subunit
Macrolides
- inhibitors of translocation
- bacteriostatic
- can treat intracellular pathogens (Mycoplasma, Legionella, Chlamydia, and Campylobacter)
Azithromycin and Clarithromycin
Modified forms of Erythromycin (type of macrolide)
Macrolide Action
Isn’t clear but is likely:
- prevent elongation
- prevent release of empty tRNA
- blockage of transpeptidation
Macrolide Resistance
- Methylation of the 23S RNA of the 50S subunit
- Hydrolysis of the lactone ring by an esterase
- Efflux of the drug
Ketolides
- inhibitors of translocation (e.g., Telithromycin)
- bind the exit tunnel of the large ribosomal subunit and block the exit of nascent polypeptides
- macrolides bind to only one domain of the 50S, these can bind to two
Streptogramins
- inhibitor of translocation
- Dalfoprisitin (binds to 50S) and Quinuprisitin (premature release of peptide chains)
- Synercid = D + Q (alone the drugs are bacteriostatic, together they are bactericidal)
