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

- Targets 23S rRNA - (e.g. erythromycin)

- Target 16S rRNA - (e.g. streptomycin)

14 - Antibiotic Resistance Flashcards by Dom Brooke

Three major modes of action of antibiotics

Cell wall synthesis inhibition
Protein synthesis inhibition
Inhibit DNA replication/repair

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Antibiotics

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

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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)

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Three mechanisms of antibiotic resistance

Inactivation of antibiotic (degradation/modification)
Efflux of antibiotic from cell - Target replacement or modification

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β−lactams

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

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β−lactam resistance

β−lactamases attack the β−lactam ring
R plasmids and transposons

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Extended spectrum β−lactamases (ESBL)

Degrades all β−lactams

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Macrolides

Targets 23S rRNA
(e.g. erythromycin)

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Macrolide resistance through degradation

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

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Macrolide resistance through modification

Macrolide phosphotransferase (Mph)

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Aminoglycosides

Target 16S rRNA
(e.g. streptomycin)

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Aminoglycoside resistance

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

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Chloramphenicol

Targets 23S rRNA

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Chloramphenicol resistance

Chloramphenicol acetyltransferase (Cat)
R plasmids and transposons

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

β−lactams
Macrolides

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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

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

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