Lecture 12 - Intro to antibiotics Flashcards
What is an antibiotic?
A chemical produced by a microorganism that kills or inhibits other microorganisms
(Synthetic or semisynthetic antimicrobials are not strictly antibiotics by definition)
It is now more commonly referring to agents that are active against bacteria and can be natural, synthetic, or semisynthetic
Where do antibiotics come from?
Antibiotics can be from other microorganisms, semi-synthetic, or synthetic
Give some examples of semi-synthetic antibiotics:
Meropenem
Amikacin
Azithromycin
Rifampicin
What are some examples of synthetic antibiotics?
Sulfa drugs (eg sulfamethoxazole)
Quinolones (eg. ciprofloxacin)
Oxazolidinones (eg. Linezolid)
What are the classes of antibiotics?
Beta-lactams
Beta-lactam/Beta-lactamase inhibitor combinations
Glycopeptides
Quinolones
Macrolides
Tetracyclines
Lincosamides
Aminoglycosides
Lipopeptides
Oxazolidinones
Streptogramines
Sulfonamides
Miscellanious
Why are carbapenums used as a last resort?
They are very broad spectrum
How is the cell wall assembled in bacteria?
Cell wall precursors are produced in the cytoplasm and then moved through the cell membrane.
How is the cell wall of bacteria produced?
Precursors are produced containing glycans and a small amino acid chain with 2 terminal D-alanines and a pentapeptide bridge which connects with the other precursors.
Carboxypeptidase cleaves 1 D-alanine and joins precursor onto the growing chain.
What enzyme joins peptidoglycans precursors to each other outside the cell membrane?
Transpeptidase
What other enzymes are involved in elongation of peptidoglycan chain?
Transglycosylase
Carboxypeptidase
How do beta lactam antibiotics work?
They inhibit binding of precursor molecules onto the elongating cell wall.
How do glycopeptides work?
They also inhibit formation of cell wall by binding the D-ala D-ala end of the precursor side chain resulting in an inability of the precursor to bind to the transpeptidases
Which 2 antibiotics work on the cell wall?
Glycopeptides
Beta lactam antibiotics
How do rifamycins work?
They inhibit the enzyme that produces mRNA (RNA polymerase) from the DNA template
How do Macrolides, Clindamycin, streptogramins, and oxazolidinones work?
They inhibit protein production by binding to the 50S ribosome and inhibiting protein elongation.
Which antibiotics inhibit protein production by binding to the 50S ribosome/?
Macrolides
Clindamycin
Streptogramins
Oxazolidinones
How do aminoglycosides work?
Bind to 30S and cause misreading of the code
Which antibiotics cause misreading of the code by binding to 30S ribisome?
Aminoglycosides
How do tetracyclines and tigecycline work?
They block binding of tRNA to 30S ribosome
Which antibiotics prevent translation by blocking tRNA binding to ribosome?
Tetracyclines
Tigecycline
What antibiotics inhibit folate synthesis?
Para aminobenzoid acid (PABA)
What is folate used for in bacteria?
They are important for the production of DNA and RNA.
What does PABA act on?
Folate synthesis
What are the enzymes involved in the synthesis of folate?
Dihydropteroate
Dihydrofolate reductase
What do sulfonamides act on?
Dihydropteroate
What does trimethoprim work on?
Dihydrofolate reductase
Is trimethoprim used alone?
Yes, but only for UTIs.
It is most often combined with other antibiotics
Which bacterial enzymes are involved in DNA replication?
DNA gyrase and DNA topoisomerase
Which antibiotics act on the bacterial enzymes involved in DNA replication?
Quinolones, they also interfere with mRNA production
What does daptomycin do?
It has a lipophilic tail which allows it to insert itself into cytoplasmic membrane. It transports potassium out of the cell depolarizing the cell membrane and thus killing it.
What is augmentin?
Amoxicillin combined with a beta lactamase inhibitor
What consideration should be made when choosing antibiotics?
That it is as specific to the pathogenic bacteria as possible
What is targeted therapy?
Specimens are collected and investigated and causative organism is isolated in the lab and tested against a range of antibiotics and based on those results the appropriate antibiotic is prescribed.
What is targeted therapy?
Specimens are collected and investigated and causative organism is isolated in the lab and tested against a range of antibiotics and based on those results the appropriate antibiotic is prescribed.
When is empirical therapy used?
When specimens are not available for lab investigation or while waiting for results of lab investigations
What is the issue with using empirical therapy?
It requires a more broad spectrum than directed therapy.
Why is narrow spectrum preferable to broad spectrum?
Broad spectrum therapy:
Encourages antibiotic resistance
Kills more normal flora
Poses greater risk of adverse effects
What is the minimum inhibitory concentration?
The minimum concentration of antibiotic that inhibits visible growth of bacteria in an in vitro system
How is the minimum inhibitory concentration decided?
Different amounts of the antibiotic are added to broth colture media. (starting from 0 and then increasing by double after the next test tube).
Standardised bacterial inoculum is added to each of the test tubes and this is incubated overnight.
How is the MIC normally tested?
Antibiotic filter paper discs added to a lawn inoculum in nutritious agar.
Antibiotic diffuses out in a gradient and bacteria receive less antibiotic further away from inoculum.
What does MIC tell us about the antibiotic we want to use?
It tells us more information about the regimen we should use and the duration it should be used.
What does MIC tell us about the bacteria?
Whether it is sensitive or resistant
What causes inherent resistant to antibiotics?
The natural competition between bacteria.
How do bacteria gain antibiotic resistance?
They may gain it through horizontal gene transfer.
Some can arise as a result of excess antibiotic use allowing only resistant individuals to survive
How do bacteria resist antibiotics?
Active removal of antibiotic from cell. (pumping antibiotic out faster than it gets in)
Inhibition of antibiotic entry to target site (changing porin site)
Production of enzymes which modify or destroy antibiotics
Alteration of antibiotic’s target so it can no longer bind
Where are antibiotic resistance genes typically found?
On plasmids
Where are antibiotic efflux pumps and porin channels located?
Gram negative outer membrane
How does pseudomonas aeruginosa confer resistance to imipenem?
Mutation in porD creates an aberrant oprD porin protein causing imipenem to no longer be able to enter the cell
What are the methods by which bacteria produce antibiotic modifying/destroying enzymes?
Modify: Aminoglycoside modifying enzymes, acetyltransfer
How can bacterial enzymes modify aminoglycosides?
They produce specialized aminoglycoside modifying enzymes
Acetyltransferases
Adenyltransferases
Phosphotransferases
How can bacterial enzymes destroy antibiotics?
Beta - lactamases (break the beta lactam ring)
How many beta lactamases have been identified?
more than 1000
What are some examples of beta-lactamases?
Penicillinases
Cephalosporinases
Carbapenemases
What are the 2 ways in which bacteria can produce enzymes to avoid antibiotic actions?
They can produce antibiotic modifying enzymes
They can produce antibiotic destroying enzymes
What percentage of staph aureus are resistant to penicillin?
80% or more
What did scientists do to make beta lactam antibiotics more effective against beta lactamases?
They produced new antibiotics that can resist the bacterial beta-lactamase.
What are the new penicillins produced to combat beta lactamases?
Methicillin
Flucloxacillin
What are the new cephalosporins produced to combat beta lactamases?
Cephalexin
and many others
What is the response of staph aureus to the new beta lactamases?
New strains of S.aureus are resistant to all beta lactams by a different mechanism.
PBP2 on has been replaced by mecA gene which encodes for PBP2a which is a lower affinity receptor for the antibiotic which can still elongate the cell wall.
What is another name for the binding site of beta lactam antibiotics?
PBP2
How are antibiotics administered?
Dose, frequency, and route of administration will vary.
When antibiotics are chosen for severe infections the choice is parenteral and then when things calm down oral is used to continue.
