Antimicrobial 2: Agents that Target Bacterial Protein Synthesis Flashcards
Antibiotics Targeting Protein Synthesis
Antibiotics/ antimicrobials that inhibit protein synthesis and are primarily bacteriostatic include drugs in the which classes?
- Tetracyclines
- Aminoglycosides
- Macrolides
- Chloramphenicol
- Oxazolidinones
- Fusidic Acid
- Streptogramins
Protein Synthesis
Describe the steps in Protein Synthesis:
DNA –> (transcription) –> RNA –> mRNA –> (translation) –> protein
(see slide 5 picture for details)
Bacterial Ribosome
what are the components?
See slide 6 picture
50S: 2 ribosomal rRNA (5S rRNA, 23S rRNA)
30S: 16S rRNA
forms 70S complex
Tetracyclines (bacteriostatic)
Drugs
See slide 7 for molecular structure.
- Tetracycline
- Oxytetracycline
- Demeclocycline
- Doxycycline
- Minocycline - BEST FOR CNS
- Tigecycline
bacteriostatic
Tetracyclines (bacteriostatic)
Effective against gram-positive & gram-negative bacteria:
Mycoplasma
Rickettsia
Chlamydia
Also effective against protozoa
Tetracyclines (bacteriostatic)
MOA
- Are taken up into susceptible organisms by active
transport and inhibit protein synthesis - Tetracyclines bind reversibly to the 16S subunit of the
30S ribosomal subunit and inhibit translation
Tetracyclines (bacteriostatic)
AE
- Staining of teeth & dental hypoplasia
- Bone deformities
Chelating calcium: stay in deposits of bones and teeth
- Bone deformities
- GI disturbances (initially via direct irritation and
followed by modification of the gut flora) - Vitamin B complex deficiency
- Hepatotoxicity
- Phototoxicity (demeclocycline)
- Vestibular disturbances (minocycline)
- Anti-anabolic actions in the host Bone marrow
depression
**Contraindicated in pregnant women, nursing mothers and children
Aminoglycosides (bactericidal in high doses & bacteriostatic)
Drugs
See slide 10 for molecular structure.
- Gentamicin
- Streptomycin
- Amikacin
- Tobramycin
- Neomycin
Aminoglycosides (bactericidal & bacteriostatic)
Characteristics
- Are more effective against gram-negative bacteria
- Their penetration through the cell membrane
depends on oxygen-dependent active transport
(minimal action against anaerobic bacteria) - Have both bacteriostatic and bactericidal actions
- Amikacin was designed as a poor substrate for
microbial enzymes that inactivate aminoglycosides
(to counteract aminoglycoside resistance)
Aminoglycosides (bactericidal & bacteriostatic)
MOA
- Bind irreversibly to the 30S ribosomal subunit and
inhibit protein synthesis (trap ribosomes at the AUG
start codon) - As cationic molecules they create fissures and pores
in the outer cell membrane, causing leakage of
intracellular contents and enhancing antibiotic
uptake
Aminoglycosides (bactericidal & bacteriostatic)
AE
- Ototoxicity
- Nephrotoxicity
- Paralysis via neuromuscular blockade (rare)
Macrolides (bacteriostatic)
Drugs
See slide 13 for molecular structure.
• Macrolides are lactone rings attached to deoxysugars
and include the following:
- Erythromycin
- Clarithromycin
- Azithromycin
- Telithromycin
- Have similar antimicrobial spectrum to that of
Penicillins, and are thus safe alternatives for
individuals showing hypersensitivity to penicillins
bacteriostatic
Macrolides (bacteriostatic)
MOA
SIGNIFICANT CYP450 INHIBITORS
- Bind the 23S rRNA molecule of the 50S ribosomal
subunit and inhibit peptidyl transferase (block transfer of new amino acids onto the growing peptide chain)
Blocks the exit channel
Macrolides (bacteriostatic)
AE
- Cholestatic jaundice (treatment > 2 wks)
bile can’t flow from liver to duodenum
- Cholestatic jaundice (treatment > 2 wks)
- GI disturbances
- Hypersensitivity reactions (rash and fever)
- Transient hearing disturbances
Chloramphenicol (bacteriostatic)
Characteristics
See slide 16 for molecular structure
- Chloramphenicol was originally isolated from cultures
of Streptomyces
- Is bacteriostatic against Gram-negative and Gram- positive organisms and should be reserved for serious infections Meningitis (when penicillin cannot be used)
Chloramphenicol (bacteriostatic)
MOA
- (same as macrolides) bind the 23S rRNA molecule of
the 50S ribosomal subunit and inhibit peptidyl
transferase (block transfer of new amino acids onto
the growing peptide chain)
Chloramphenicol (bacteriostatic)
AE
- ‘grey baby’ syndrome, grey colour of skin, vomiting, diarrhea, mortality
- Severe depression of bone marrow causing
- pancytopenia, decrease in all blood cells
Oxazolidinedione (bacteriostatic)
Consider the first truly new class of antibacterials to reach the market -
Drug
See slide 18 for molecular structure
Linezolid
Oxazolidinedione (bacteriostatic)
Charactistics
- Active against wide variety of Gram-positive bacteria
and useful against drug-resistant bacteria such as
MRSA
Oxazolidinedione (bacteriostatic)
MOA
- Inhibit bacterial protein synthesis via a novel
mechanism involving antagonism of the N-
formylmethionyl-tRNA binding to the 70S ribosome
Oxazolidinedione (bacteriostatic)
PK?
- Linezolid has 100% oral bioavailability
- Linezolid is also a weak monoamine oxidase inhibitor
Oxazolidinedione (bacteriostatic)
AE
- Thrombocytopenia
- Serotonin syndrome
- Hyperlactatemia
- Diarrhea
- Nausea
- Rash
- Dizziness
Other Agents Targeting Protein Synthesis
Fusidic Acid (bacteriostatic)
MOA
See slide 21 for molecular structure
- Steroid antibiotic against Gram-positive bacteria that
inhibits bacterial protein synthesis by interfering with translation - steroid backbone
Other Agents Targeting Protein Synthesis
Fusidic Acid
AE
- Jaundice
- GI disturbances
Other Agents Targeting Protein Synthesis
Streptogramins (Quinupristin & Dalfopristin) -
(bacteriostatic)
MOA
See slide 22 for molecular structure
- Cyclic peptides that inhibit bacterial protein synthesis
by binding to the 50S subunit of the bacterial ribosome
(Gram-positive organisms)
Other Agents Targeting Protein Synthesis
Streptogramins (Quinupristin & Dalfopristin) -
(bacteriostatic)
AE
- Inflammation at infusion site (*arthralgia and *myalgia)
- Nausea, vomiting & diarrhea
Other Agents Targeting Protein Synthesis
Clindamycin (a lincosamide) - (bacteriostatic)
MOA
See slide 23 for molecular structure
- Same as macrolides & chloramphenicol
- Inhibit bacterial protein synthesis
- Bind the 23S rRNA molecule of the 50S ribosomal
subunit and inhibit peptidyl transferase (block transfer
of new amino acids onto the growing peptide chain)
Other Agents Targeting Protein Synthesis
Clindamycin (a lincosamide) - (bacteriostatic)
AE
- Potentially lethal psuedomembranous colitis (toxin-
forming C. difficile)
- Potentially lethal psuedomembranous colitis (toxin-
- GI disturbances (uncomfortable diarrhea)
Quinolones (Bactericidal)
Drugs
Effective against both Gram-positive & Gram-negative bacteria
See slide 24 for molecular structure
Quinolones are broad-spectrum fluorinated) and include; • Nalidixic Acid • Ciprofloxacin • Levofloxacin • Ofloxacin • Norfloxacin • Moxifloxacin
good for UTI
Quinolones (Bactericidal)
MOA
- Inhibit topoisomerase II (bacterial DNA gyrase which cuts open DNA and reseals it) and topoisomerase IV
- Prevent negative supercoiling of DNA (required to
allow transcription or replication of DNA) by DNA
gyrase. - Prevent topoisomerase IV mediated decatenation of
daughter DNA molecules.
Quinolones (Bactericidal)
AE
- *Arthropathy
- *Convulsions (can be exacerbated with concurrent use of theophyllines)
- due to point mutations of DNA gyrase enzyme
- high conc in kidneys for excretion
- GI disturbances
- Hypersensitivity reactions (rashes)
- Headache and dizziness
Summarize Antibacterials that interfere with bacterial protein synthesis : (6)
- Tetracyclines bind reversibly to the 16S subunit of the
30S ribosomal subunit and inhibit translation - Aminoglycosides bind irreversibly to the 30S ribosomal
subunit and inhibit protein synthesis (trap ribosomes at
the AUG start codon) - Macrolides bind the 23S rRNA molecule of the 50S
ribosomal subunit and inhibit peptidyl transferase
(block transfer or new amino acids onto the growing
peptide chain) - Chloramphenicol & clindamycin have a similar
mechanism of action as the macrolide antibiotics - Oxazolidinones are the newest class of antibacterials,
which inhibit bacterial protein synthesis via a novel
mechanism involving antagonism of the N-
formylmethionyl-tRNA binding to the 70S ribosome - Quinolines, which inhibit topoisomerase II (bacterial
DNA gyrase) and thereby prevent supercoiling of
DNA, leading to cessation of transcription/replication
of DNA
why do antibiotics have hard time targeting G- bac ?
- outer membrane makes it hard for drugs to reach bacterium
- outer membrane has porin channels that prevent entry of chemicals
