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.
Describe the properties of tetracyclines.
Very broad spectrum activity.
Good activity against gram-positive and gram negative bacteria ( rickettsia, chlamydia, mycoplasma, and spirochaetes).
Therefore it’s effective against intracellular pathogens.
All have similar mechanisms of activity.
Distinguished more by their pharmacokinetic activities.
Explain the name tetracycline.
Four (tetra)
Cyclic rings (cyclines)
Which tetracyliens are the most used? Why?
doxycycline and minocycline (semi-synthetic)
long half-life within the body- only need to be taken once or twice per day.
they have lower renal toxicity and are better absorbed than other tetracyclines when taken orally.
Side effects of tetracyclines.
Why is its use avoided in pregnant women?
Gastrointestinal disturbances
Liver damage possibly leading to Liver failure in severe cases
Vertigo
Phototoxicity
Deposition of the antibiotic in the bones and teeth - avoided for pregnant women as this poses a risk to the development of these structures in a fetus
tetracycline mechanism of action
tetracyclines will be concentrated within the cell by active transport where, by interaction with the 30S subunit, they will interfere with the binding of the aminoacyl tRNA to the A-site on the ribosome
Bacteriostatic mechanism - doesn’t kill bacteria just stops them from growing
Tetracycline resistance
New protein produced by the bacterium that stops the intracellular accumulation of the drug via forming a highly efficient efflux mechanism
Cross-resistance occurs because tetracyclines have similar structures - causing resistance to nearly to all tetracyclines.
What is Tigecycline
The most recent tetracycline to be developed.
How does Tigecycline avoid resistance mechanism of bacteria
Can avoid the resistance mechanism of rapid efflux - has an extremely high affinity for the ribosome resulting in tight binding and therefore retention in the cell.
What bacteria is Tigecycline active against?
several multiply resistant Gram negative bacteria, including Acinetobacter species, as well as MRSA.
What mechanisms has caused resistance to occur to Tigecycline?
mutation of the efflux pumps to make them more effective at clearing the antibiotic.
Also TetX enxyme in Ancientobacter sp. that encodes for an oxireductase - able to modifiy tigecycline antibiotic as well as other tetracyclines. This causes oxygen-dependent destruction of tetracyclines caused by TetX
How is the tetX protein transfered between bacteria?
Gene coding for tetX found on plasmids and in transposons found in Bacteroides strains likely transferred to Acinetobacter species via horizontal gene transfer.
What is chloramphenicol?
Broad-spectrum antibiotic
Properties of Chloramphenicol
with a simple structure making it easy to chemically synthesise.
Able to diffuse well into cerebospinal fluid
Can penetrate into host cells- ideal to treat intracellular infections such as bacerial meningitis
Bacteria that Chloramphenicol can act on
broad host range including Gram positives, Gram-negatives, rickettsia, and chlamydia, making it able to treat intracellular infections
Chloramphenicol mechanism of action
bind to the 50S subunit of the ribosome and inhibit the peptidyl transferase reaction- a peptide bond is formed between two amino acids on the 70S ribosome.
Bacteriostatic - bactericidial in some bacterial species.
What bacterial infections can Chloramphenicol treat?
typhoid fever, typhus, and other intracellular bacterial infections such as bacterial meningitis.
Chloramphenicol resistance
Due to bacterial enzymes acetylating the two hydroxyl groups of chlorampheimcol - makes it unable to bind the bacterial ribosomes and unable to block protein synthesis.
Resistance is rare but resistant Typhoid strains cause probelms where the strains are endemic
Chloramphenicol side effects
Major draw back as it has a lot of side effect
diarrhoea, nausea, vomiting and headaches but major side effects include a dose dependent bone marrow depression potentially leading to the potentially fatal aplastic anaemia
use of chlorampheniccol in hopsitals
relegated for life threatening conditons/ highly resistant bacterium
What is grey baby syndrome
Common syndrome caused by side effects of chloramphenicol when it was used to treat menigitis due to the neonates relative inability to clear the drug compared with an adult, if dosage is not correctly adjusted and monitored a build-up of the potentially toxic compound may occur leading to hypotension, cardiovascular collapse and death if not recognise
Baby turns a pla egrey colour
