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MICR3330 > 14 - Antibiotic Resistance > Flashcards

14 - Antibiotic Resistance Flashcards

1
Q

Three major modes of action of antibiotics

A
  • Cell wall synthesis inhibition
  • Protein synthesis inhibition
  • Inhibit DNA replication/repair
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2
Q

Antibiotics

A

A chemical substance produced by microorganisms that inhibit (bacteriostatic) or kill (bactericidal) other microorganisms.

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3
Q

Development of antibiotic resistance

A
  • 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)
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4
Q

Three mechanisms of antibiotic resistance

A
  • Inactivation of antibiotic (degradation/modification)
  • Efflux of antibiotic from cell - Target replacement or modification
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5
Q

β−lactams

A
  • Derived from penicillin
  • Different types of β−lactams have different R
    groups attached the β−lactam ring
  • Target transpeptidase (PBP)
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6
Q

β−lactam resistance

A
  • β−lactamases attack the β−lactam ring
  • R plasmids and transposons
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7
Q

Extended spectrum β−lactamases (ESBL)

A

Degrades all β−lactams

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8
Q

Macrolides

A
  • Targets 23S rRNA
  • (e.g. erythromycin)
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9
Q

Macrolide resistance through degradation

A
  • Erythromycin esterase (EreB) which hydrolyses the macrolide ring lactone structure
  • R plasmid and transposon encoded
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10
Q

Macrolide resistance through modification

A

Macrolide phosphotransferase (Mph)

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11
Q

Aminoglycosides

A
  • Target 16S rRNA
  • (e.g. streptomycin)
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12
Q

Aminoglycoside resistance

A
  • Inactivated through modification of the hydroxyl and amino groups
  • Phosphotransferase (Aph)
  • Adenyltransferases (Aad)
  • Acetyltransferases (Aac)
  • R plasmids and transposons
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13
Q

Chloramphenicol

A

Targets 23S rRNA

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14
Q

Chloramphenicol resistance

A
  • Chloramphenicol acetyltransferase (Cat)
  • R plasmids and transposons
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15
Q

Examples of antibiotic resistance through inactivation of the antibiotics (degradation)

A
  • β−lactams
  • Macrolides
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16
Q

Examples of antibiotic resistance through inactivation of the antibiotics (Modification)

A
  • Aminoglycosides
  • Chloramphenicol
  • Macrolides
17
Q

Efflux pumps

A

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

18
Q

Five major families of antibiotic efflux

A
  • Determined by structure
  • Usually pumps out more than
    one antibiotic
19
Q

Example of plasmid born efflux pumps

A

18 different tetracycline resistance pumps encoded on transposons

20
Q

Vancomycin

A

Binds D-Ala-D-Ala termini of peptidoglycan with HIGH affinity preventing cross-linking and increasing sensitivity to osmotic stress

21
Q

Vancomycin resistance

A
  • 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
22
Q

Fourvan genes

A
  • VanH, X, Y and A
  • Found on Integrons
23
Q

Tetracycline

A

Target 16S rRNA

24
Q

Tetracycline resistance

A
  • Ribosomal protection protein
    that inhibits access to the
    binding site
  • R plasmids, transposons and integrons
25
Q

β−lactam target replacement/modification (e.g methicllin)

A
  • Target penicillin binding proteins (PBP)
  • Low affinity PBP used as target instead (e.g. MecA)
26
Q

Mutation of the target

A

Mutation of the target protein can lead to less binding of the antibiotic to the target thereby creating antibiotic resistance

27
Q

Example of mutation of target

A
  • Novobiocin inhibits DNA gyrase
  • Mutant DNA gyrase subunit B
    contains changes in the amino
    acid sequence, decreasing binding of novobiocin
28
Q

Sources of antibiotic resistance

A
  • R plasmids
  • Transposons
  • Integrons
29
Q

R plasmids

A
  • Move from cell to cell by conjugation or transformation
  • Only common feature is carriage of an antibiotic resistance marker
  • Vertical transfer to daughter cells
30
Q

Transposons

A
  • Move from genome to plasmids by transposition
  • Vertical transfer to daughter cells
31
Q

Integrons

A
  • 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
32
Q

What are R plasmids derived from

A
  • Conjugative plasmids
  • Mobilizable, non-conjugative plasmids
33
Q

Mobilisation of R plasmids

A
  • 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
34
Q

IncW plasmids

A
  • Broad host range
  • Conserved genetic arrangement (synteny) of the conjugation gene module (necessary to build the conjugation pilus)
  • Basic building block for R plasmids
35
Q

Features of gene capture by integrons

A
  • Integrase gene (intI)
  • A nearby recombination site (attL)
  • A promoter, P
  • Gene cassette
36
Q

Gene cassette

A
  • Free circular piece of DNA, not replicated or transcribed
  • A recombination site (attC)
37
Q

Steps in gene capture by integrons

A
  1. Integrase mediates recombination at
    attL and attC sites resulting in insertion
    of gene cassette downstream of the promoter
  2. Transcription of Gene cassette from promoter
  3. Integrase mediates recombination at attL-attC sites which result in rearrangement or excision of gene cassettes
38
Q

R plasmids/integrons arising in environment

A
  • 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
39
Q

Why dont we just stop using antibiotics

A

Prevalence of antibiotic resistance does not disappear when
antibiotic is no longer used

MICR3330 (29 decks)

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