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Genetics of antibiotic resistance. Genetics of prokaryotic genomes What is an antibiotic? How do antibiotics work? How is antibiotic action measured? How does antibiotic resistance develop?. Prokaryotic cell structures. http://biology.about.com/lr/prokaryotes/489687/1/.

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genetics of antibiotic resistance
Genetics of antibiotic resistance
  • Genetics of prokaryotic genomes
  • What is an antibiotic?
  • How do antibiotics work?
  • How is antibiotic action measured?
  • How does antibiotic resistance develop?
prokaryotic cell structures
Prokaryotic cell structures

http://biology.about.com/lr/prokaryotes/489687/1/

prokaryotic and eukaryotic cells
Prokaryotic and eukaryotic cells
  • Eukaryotic cells have a true nucleus, bound by a double membrane.
  • Eukaryotic DNA is linear; prokaryotic is circular.
  • Prokaryotes have no histones or nucleosomes.
  • Eukaryotic ribosomes are larger and more complex.
  • Prokaryotes have no membrane-bound organelles.

www.cod.edu/people/faculty/fancher/prokeuk.htm

gram positive cell walls
Gram positive cell walls

N-Acetyl glucosamine

N-acetyl muramic acid

Two tetrapeptide chains crosslinked by peptide

Peptoglycan layers

Plasma membrane showing lipid bilayer

Bacterium showing outer cell wall and inner plasma membrane

Wikipedia

gram negative outer layers
Gram negative outer layers

Lipopolysaccharides

Wikipedia

how many bacterial genomes have been sequenced
How many bacterial genomes have been sequenced?

23,503 prokaryotic genomes

with sequence information in Entrez database

as of March 27, 2013

http://www.ncbi.nlm.nih.gov/genomes/lproks.cgi

prokaryotic genomes are circular
Prokaryotic genomes are circular
  • Annotation identifies unusual features:
  • different AT/GC ratios,
  • sequences related to antibiotic or heavy metal resistance,
  • similarities to exogenous elements,
  • etc.
prokaryotic genomes have many heterologous sequences
Prokaryotic genomes have many heterologous sequences

1 & 2 = Coding regions

3= RNA encoding

4= special features 300 strain

5- 8 = comparison of other strains

9 = SNPs vs. COL strain

10 & 11 = synonymous and non

SNPs vs. COL strain

Enright, M.C. (2006) Genome of an epidemic community-acquired MRSA. The Lancet 367, 705-706

choosing antibiotic targets
Choosing antibiotic targets

Why target cell wall biosynthesis?

Walsh, C. (2003) Where will new antibiotics come from? Nat Rev Micro 1, 65-70

why protein synthesis
Why protein synthesis?

Why do these antibiotics only work against prokaryotes?

Walsh, C. (2003) Where will new antibiotics come from? Nat Rev Micro 1, 65-70

n ucleic a cid b iosynthesis
Nucleic Acid Biosynthesis?

Why do these antibiotics only work against prokaryotic synthesis?

Walsh, C. (2003) Where will new antibiotics come from? Nat Rev Micro 1, 65-70

mechanisms of resistance
Mechanisms of resistance

Arrias and Murray. NEJM . 360(5), 2009.

mechanisms of resistance1
Mechanisms of resistance
  • Pump it out
  • Disarm or modify it
  • Change the target to reduce binding
  • Over express the target
quantifying antibiotic resistance
Quantifying antibiotic resistance

Bacterial “lawn”

Bacterial “lawn”

Antibiotic disc

Liu, X., et al. (2008) Proceedings of the National Academy of Sciences 105, 13321-13326

dna t ransposons plasmids phages
DNA, transposons, plasmids, phages…

Many prokaryotes take up DNA promiscuously and have mechanisms to incorporate the DNA into the chromosome or plasmids

+

Antibiotic resistance can be a clear selective advantage

Miriagou, V., et al. (2006) Microbes Infect 8, 1923-1930

integrons
Integrons

Recombination site

Chromosomal “target” sequences

Site-specific recombinase

Addition of exogenous sequences by recombination

Boucher, Y., et al. (2007) Trends in Microbiology 15, 301-309

how do integrons grow and change
How do integrons grow and change?

Step 1, integration

Step 2, integration & addition of heterologous sequences

Boucher, Y., et al. (2007) Trends in Microbiology 15, 301-309

why are antibiotic resistance genes so varied
Why are antibiotic resistance genes so varied?

Once within the cell, recombination allows reshuffling, addition and easy incorporation into the central genome

Miriagou, V., et al. (2006) Microbes Infect 8, 1923-1930

prokaryotic genomes many sequences from outside
Prokaryotic genomes – many sequences from “outside”

Heterologous sequences often related to antibiotic resistance, “landing pads” for integration of new sequences, etc.

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