0521 - Antibiotic Resistance Flashcards
Why is antibiotic resistance significant in modern medicine?
You use it, you lose it. 80% used in animals, big source of resistance.
Massive problem for multiple medical procedures, including immunosuppressed patients (chemo, haematopoietic/organ transplants, bowel surgery).
What are the two forms of antibiotic resistance?
Can be intrinsic or extrinsic.
Intrinsic - bacteria naturally resistant to a given antibiotic - predictable and not transmitted.
Extrinsic - worrying one. Genetic mutation can spread between bacteria via plasmids.
How are antibiotic resistance genes developed in bacteria?
Vertical evolution - chance mutations (natural), allows for natural selection and survival of the fittest, while maintaining virility. Very time consuming, takes several generations.
Horizontal acquisition - explosion of resistance. Transfer of resistance genes from other organisms, generally via plasmids.
What is a plasmid?
Extrachromosomal DNA, that can replicate independent of chromosomes. It contains non-essential or adaptational genes, such as resistance (c.f. essential genes on chromosome). Can transfer even between species of bacteria.
How can DNA move in/out of bacterial chromosomes and plasmids?
Integrons - insert resistance at a specific point in the genome. More specific than transposons.
Transposons - DNA that can change its position within the genome depending on a target sequence, allowing it to go into another site and carry the resistance.
Bacteriophages - Phage DNA can contain resistance genes and be incorporated into bacterial genome.
List the four mechanisms of spreading antibiotic resistance
Vertical evolution/gene transfer Transformation Transduction Conjugation (most common) (all forms of horizontal acquisition)
What is Transformation as a mechanism of antibiotic resistance?
Uptake of ‘naked’ DNA from environment, and incorporating into genome. Used by strep pneumoniae to acquire penicillin resistance.
DNA must be from same or related bacteria to be integrated into the chromosome.
What is transduction as a mechanism of antibiotic resistance?
Transfer of DNA from one bacterium to another via bacteriophages. Phage DNA can contain resistance genes and is incorporated into bacterial chromosome.
Requires phage infection, so limited by the host-range of the bacteriophage, and require target sequences of DNA - so more likely in related bacteria
What is conjugation as a mechanism of antibiotic resistance?
Transfer of plasmid DNA between bacteria directly. Plasmid DNA containing resistance can then be integrated into DNA of recipient.
Most efficient way, and most significant mechanism for antibiotic resistance clinically.
Not many limitations, allows resistance to spread from unrelated bacteria.
How do antibiotics act?
Inhibit Protein synthesis (act on 50S/30S)
Inhibit Cell wall synthesis
Nucleic acid inhibition (DNA, RNA, or Folic Acid)
What are the four mechanisms of antibiotic resistance?
Drug inactivating enzyme
Alteration in target molecule - drug can’t bind to target.
Decreased uptake - don’t let drug into cell
Increased elimination - efflux pump.
Discuss mechanisms of antibiotic resistance in staph aureus
Penicillin - uses a beta lactamase to destroy beta lactam ring and inactivate the drug.
Methicillin - uses the mecA gene to change the conformation of penicillin binding site to prevent binding of ALL beta lactams (target alteration)
Intermediate vancomycin resistant - thicken the cell wall, which reduces ability of antibiotic to get into the bacteria and hit the binding site (decreased uptake).
What is the difference between MR-MRSA and NMR-MRSA?
MR-MRSA is multiresistant - resistant to 3 or more non-beta lactam classes. Typically healthcare acquired, with limited treatment options (vancomycin, rifampicin)
NMR-MRSA is non-multiresistant - typically community acquired and remains sensitive to most non-beta lactam antibiotics.
Discuss mechanisms of antibiotic resistance in strep pneumoniae
Penicillin - Change in PBP associated with several gene mutations. Not becoming outright resistant, but becoming less susceptible at this stage. Becomes tricky in meningitis - can’t get high enough doses into CSF.
Macrolide and clindomycin type:
- Change in 50s ribosome binding site via rRNA methylase (macrolide and clindamycin).
- Mef efflux pumps (just for macrolide - Macrolide Efflux Pump)
Discuss mechanisms of antibiotic resistance in enterococcus sp
Intrinsically resistant to many AB’s, including cephalosporins and most non-beta lactam antibiotics.
Vancomycin - Changed binding site, from D-Ala-D-Ala to D-Lac, through VanA or VanB gene.
