14 - Antibiotic Resistance Flashcards
Three major modes of action of antibiotics
- Cell wall synthesis inhibition
- Protein synthesis inhibition
- Inhibit DNA replication/repair
Antibiotics
A chemical substance produced by microorganisms that inhibit (bacteriostatic) or kill (bactericidal) other microorganisms.
Development of antibiotic resistance
- Antibiotic-producing strains are resistant to their own antibiotics
- Co-evolution of antibiotic producing and non producing strains has led to
intrinsic resistance (chromosomally encoded) - Intensive use of antibiotics
has led to acquired resistance (Mobile genetic elements)
Three mechanisms of antibiotic resistance
- Inactivation of antibiotic (degradation/modification)
- Efflux of antibiotic from cell - Target replacement or modification
β−lactams
- Derived from penicillin
- Different types of β−lactams have different R
groups attached the β−lactam ring - Target transpeptidase (PBP)
β−lactam resistance
- β−lactamases attack the β−lactam ring
- R plasmids and transposons
Extended spectrum β−lactamases (ESBL)
Degrades all β−lactams
Macrolides
- Targets 23S rRNA
- (e.g. erythromycin)
Macrolide resistance through degradation
- Erythromycin esterase (EreB) which hydrolyses the macrolide ring lactone structure
- R plasmid and transposon encoded
Macrolide resistance through modification
Macrolide phosphotransferase (Mph)
Aminoglycosides
- Target 16S rRNA
- (e.g. streptomycin)
Aminoglycoside resistance
- Inactivated through modification of the hydroxyl and amino groups
- Phosphotransferase (Aph)
- Adenyltransferases (Aad)
- Acetyltransferases (Aac)
- R plasmids and transposons
Chloramphenicol
Targets 23S rRNA
Chloramphenicol resistance
- Chloramphenicol acetyltransferase (Cat)
- R plasmids and transposons
Examples of antibiotic resistance through inactivation of the antibiotics (degradation)
- β−lactams
- Macrolides
Examples of antibiotic resistance through inactivation of the antibiotics (Modification)
- Aminoglycosides
- Chloramphenicol
- Macrolides
Efflux pumps
Use the proton motive force or
ATP to pump drugs out of the cytoplasm thereby decreasing the intracellular concentration of drug to non-therapeutic levels
Five major families of antibiotic efflux
- Determined by structure
- Usually pumps out more than
one antibiotic
Example of plasmid born efflux pumps
18 different tetracycline resistance pumps encoded on transposons
Vancomycin
Binds D-Ala-D-Ala termini of peptidoglycan with HIGH affinity preventing cross-linking and increasing sensitivity to osmotic stress
Vancomycin resistance
- Target modified to N-acyl-D-Ala-D-Ala or N-acyl-D-Ala-D Lac which bind vancomycin at LOW affinity
- Through acquisition of fourvan genes
Fourvan genes
- VanH, X, Y and A
- Found on Integrons
Tetracycline
Target 16S rRNA
Tetracycline resistance
- Ribosomal protection protein
that inhibits access to the
binding site - R plasmids, transposons and integrons
β−lactam target replacement/modification (e.g methicllin)
- Target penicillin binding proteins (PBP)
- Low affinity PBP used as target instead (e.g. MecA)
Mutation of the target
Mutation of the target protein can lead to less binding of the antibiotic to the target thereby creating antibiotic resistance
Example of mutation of target
- Novobiocin inhibits DNA gyrase
- Mutant DNA gyrase subunit B
contains changes in the amino
acid sequence, decreasing binding of novobiocin
Sources of antibiotic resistance
- R plasmids
- Transposons
- Integrons
R plasmids
- Move from cell to cell by conjugation or transformation
- Only common feature is carriage of an antibiotic resistance marker
- Vertical transfer to daughter cells
Transposons
- Move from genome to plasmids by transposition
- Vertical transfer to daughter cells
Integrons
- Modified form of a transposon which has the capacity to capture genes and integrate them
- Will move when it is located on a plasmid or transposon
What are R plasmids derived from
- Conjugative plasmids
- Mobilizable, non-conjugative plasmids
Mobilisation of R plasmids
- Carry mobilization region (mob) encoding specific relaxosome components and oriT
- No conjugation machinery of its own
- Stable maintenance of both F and R plasmids is determined by incompatibility (Inc) groups
IncW plasmids
- Broad host range
- Conserved genetic arrangement (synteny) of the conjugation gene module (necessary to build the conjugation pilus)
- Basic building block for R plasmids
Features of gene capture by integrons
- Integrase gene (intI)
- A nearby recombination site (attL)
- A promoter, P
- Gene cassette
Gene cassette
- Free circular piece of DNA, not replicated or transcribed
- A recombination site (attC)
Steps in gene capture by integrons
- Integrase mediates recombination at
attL and attC sites resulting in insertion
of gene cassette downstream of the promoter - Transcription of Gene cassette from promoter
- Integrase mediates recombination at attL-attC sites which result in rearrangement or excision of gene cassettes
R plasmids/integrons arising in environment
- IncW plasmids were in soil/water organisms
- Then collected AMR on transposons/integrons
- Then shared the InW plasmid with related organisms in the gut
- Now in clinically relevant bacteria
Why dont we just stop using antibiotics
Prevalence of antibiotic resistance does not disappear when
antibiotic is no longer used
