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

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Genetics of antibiotic resistance

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  1. 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?

  2. Prokaryotic cell structures http://biology.about.com/lr/prokaryotes/489687/1/

  3. 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

  4. 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

  5. Gram negative outer layers Lipopolysaccharides Wikipedia

  6. 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

  7. 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.

  8. 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

  9. Choosing antibiotic targets Why target cell wall biosynthesis? Walsh, C. (2003) Where will new antibiotics come from? Nat Rev Micro 1, 65-70

  10. 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

  11. 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

  12. Mechanisms of resistance Arrias and Murray. NEJM . 360(5), 2009.

  13. Mechanisms of resistance • Pump it out • Disarm or modify it • Change the target to reduce binding • Over express the target

  14. Quantifying antibiotic resistance Bacterial “lawn” Bacterial “lawn” Antibiotic disc Liu, X., et al. (2008) Proceedings of the National Academy of Sciences 105, 13321-13326

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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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