RO L7 Flashcards
Antibiotic Resistance
A microbe that was previously
susceptible to an antibiotic is no longer affected by it
Bacteria become resistant to Antibiotics by:
- Releasing enzymes that can destroy/inactivate the
antibiotic - Alteration of Antibiotic Targets
- Prevention of Antibiotic Access to Target
- Releasing enzymes that can destroy/inactivate the antibiotic
Enzymes can be produced by the bacteria which degrade the
antibiotic directly or modify it so that it can no longer
interact with its target
Examples:
β-lactamases (penicillinase) degrade penicillins and
cephalosporins by hydrolysing the β-lactam ring
Aminoglycoside-modifying enzymes can reduce the activity of
the antibiotic by attaching chemical groups which prevent
binding to its target (steric hindrance)
The effect of β-lactamase on Penicillin
Enzyme can be transmitted by plasmids
Can inactivate other antibiotics that contain a β-lactam ring,
such as cephalosporins (cross resistance)
- Alteration of Antibiotic Targets
Changes to the structure of the target (without loss of function)
which prevent efficient binding of the antimicrobial agent.
These changes can be a result of DNA alteration or posttranslational modification
Example:
Single amino-acid change in bacteria ribosomal protein which
prevents efficient binding of macrolides.
Resistance to erythromycin, rifamycin, and antimetabolites has
developed by this mechanism
- Alteration of Antibiotic Targets
Methicillin-resistant Staphylococcus aureus (MRSA)
- Methicillin is resistant to degradation by β-lactamases
- PBP2 (cell wall biosynthesis): target of β-lactam
antibiotics (e.g. methicillin) - Acquisition of gene encoding non-native version PBP2a
(lower affinity for β-lactams) - Active site (nucleophilic serine) less accessible to βlactams
- Prevention of Antibiotic Access to Target
This can be achieved by:
- Reduced permeability: Alteration of pores/channels to
prevent antibiotics from crossing the membrane and
reaching their target
- Increased efflux: Over-expression of efflux pumps that
actively transport antibiotics out of the bacterial cell
Resistance to tetracyclines, quinolones and some
aminoglycosides has occured via this method
- Prevention of Antibiotic Access to Target
Efflux-mediated antibiotic resistance
Multidrug resistance (MDR)
pumps can confer resistance to a
range of antibiotics
Found in some isolates of
Enterococcus faecium, S. aureus,
Klebsiella pneumoniae,
Acinetobacter baumannii,
P. aeruginosa, Enterobacter sp
Development of Antibiotic Resistance
Genetic mechanisms:
Involves genetic changes followed by natural selection
Spontaneous changes to chromosomal DNA: Leads to
alteration in amino
acid sequence of protein product –can alter target (E.g. ribosomal proteins
altered so antibiotic can no longer bind); transferred vertically
Acquisition of plasmids
: Extra-chromosomal DNA containing resistance
genes can be acquired
Development of Antibiotic Resistance
Resistance (R) Plasmids: Discovered in Shigella in Japan in 1959
2 components:
1. Resistance Transfer Factor (RTF) which includes genes required for
conjugation
2. One or more resistance (R) genes/r-determinants: Each R gene contains
information that confers resistance to one type of antibiotic or heavy
metal; transferred horizontally by conjugation, transformation, or
transduction; can be multiple R genes per plasmid
R genes can also be transferred to other plasmids, or to chromosomal
DNA, or to phage DNA –transposition (transposons)
Mechanism of Bacterial Conjugation
for Plasmid transfer
Plasmids can carry genes encoding enzymes that can degrade/modify antibiotics
E.g. - Klebsiella pneumonia and E. coli plasmids can carry carbapenemase gene
- β-lactam resistance can be acquired through uptake of plasmid carrying βlactamase enzyme
Fitness cost for plasmid retention (selection)
Minimising the Development of
Antibiotic Resistance
- Completing courses of antibiotics: Inhibit or kill pathogenic bacteria
population rather than just decreasing numbers - Administering two or more drugs simultaneously: Can have a
synergistic effect (e.g. different targets); Reduced likelihood of
resistance - Restriction of use to essential cases only: Limit use for viral
infections and in animal feed - Use of narrow-spectrum antibiotics (preserve microflora)
- Keeping reserve antibiotics
Antibiotic tolerance
A population of bacteria without a resistance mechanism
that can survive antibiotic treatment for a longer duration
