Antibiotics 2 Flashcards
Protein Synthesis
What does the inhibition of bacterial protein synthesis rely on?
The difference between ribosome structures when comparing bacteria and mammals.
Structural differences between the two types of ribosomes as well as access to/ affinity for those ribosomal targets are used by antibiotics which target bacterial protein synthesis without affecting mammalian systems.
What are the two types of ribosomes? What systems ar they found in and what are their subunits?
Bacteria: 70S ribosomes that are made of 50S and 30S subunits
Mammalian systems: 80S ribosomes made of 60S and 40S subunits
What are aminoglyocosides? List some examples.
Aminoglycosides are natural or semisynthetic antibiotics derived from actinomycetes.
Streptomycin – first synthesized aminoglycoside
Gentamicin – synthesized from micromonospora purpurea
Amikacin – semisynthetic (derived from a naturally occurring antibiotic ( kanamycin) but subsequently altered to make it less susceptible to bacteria resistance mechanisms)
Describe the general structure of aminogycosides.
All aminoglycosides have a modified cyclohexane ring and amino sugars – polycationic in nature
How are aminoglycosides administered?
Poorly absorbed when taken orally – administered by injection
Describe the spectrum of aminoglycosides. What bacteria are they most or least effective to?
Potent broad-spectrum agents due to their mode of action.
Most effective against negative bacilli and staphylococci.
Poorly active against anaerobes and streptococci but able to act synergistically in combination with B-lactam antibiotics (e.g penicillin) making it effective against some streptococci.
penetrate poorly into mammalian cells - Ineffective against bacteria that infect intracellularly.
Describe the use of Aminoglycosides in hospitals. Name the type of infections Aminoglycosides are used for.
Generally used when other antibiotic therapies have failed
Only used for severe gram-negative septicemias or in combination with B-lactams for endocarditis/ staphylococcus aureus-based septicemia
Why is the use of Aminoglycosides limited?
Limited use: Can cause severe side effects and the window between concentrations required for effective treatment and toxicity to the host is narrow
Describe the toxic side effects of aminoglycosides. What aminoglycoside is the safest and which is the most harmful?
Aminoglycosides are toxic to the ear causing auditory / vesticular damage (dizziness and vertigo) and potentially cause deafness
Toxicity to the kidneys also possible – acute renal insufficiency and tubular necrosis – potentially causing kidney failure
Neomycin – most toxic aminoglycoside
Streptomycin –safest
Describe the Aminoglycoside mechanism of action.
Bactericidal - Act by binding bacterial 30S ribosomal subunit, interfering with mRNA binding and preventing the formation of initiation complexes - prevents protein synthesis.
Cause misreading of mRNA codons leading to defective protein production- can affect membrane integrity because of the production of defective proteins.
May inhibit the translocation step in polypeptide synthesis.
Name the mechanism that bacteria use to uptake aminoglycosides. Which bacteria can’t do this effectively?
Via energy-dependent self-promoted uptake mechanisms.
Streptococci and many anaerobes don’t contain quinones - cant take up aminoglycosides efficiently.
Describe the uptake of aminoglycosides into the cell. How does this allow antibiotics to work synergistically?
Cationic aminoglycoside interacts with sites on the bacterium’s outer membrane.
Divalent cations on the bacterium membrane cross-bridge next to lipopolysaccharide molecules causing destabilization of the outer membrane.
This allows the uptake of the aminoglycoside.
Evidence suggests that other molecules in the immediate vicinity like other antibiotics can use this membrane disruption to cross the barrier - two antibiotics can work synergistically.
Describe the bacterial mechanisms of resistance to aminoglycosides.
Alteration to the bacterial ribosomal structure changes the target of action and prevents the binding of the antibiotic.
Production of aminoglycoside-modifying enzymes that react with groups on the aminoglycoside molecule to give an altered aminoglycoside molecule. This competes with unmodified aminoglycoside for uptake into the cell which can block uptake entirely.
What are the three main types of enzymes that make modifications to aminoglycosides?
Phosphotransferases: Attach a phosphate group onto the exposed hydroxyl group of the aminoglycoside.
Adenyltransferfases: Attach a nucleotide to an exposed hydroxyl group on the antibiotic.
Acetyltransferases: Transfer acetate from acetyl-CoA onto an amino group of the aminoglycoside.
When was the first tetracycline discovered?
In 1948 as a product of streptomyces aureofaciens.
