Evolution and Ecology of Antibiotic Resistance

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Evolution and Ecology of Antibiotic Resistance
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Background

• Time scale
• Evolution of pathogenesis millions of years
• Evolution of a/b resistance 60 years?
• Between 1949 and 1951 in Japan, sulfonamide
  resistance in Shigella rose from 10 to 90.
• Similar trends for almost all other antibiotics
  and pathogens
• Multidrug resistance never anticipated
• 5 yrs after streptomycin, tetracycline,
  chloramphenicol were massively introduced,
  multi-drug resistant Shigella was identified
• Hints about mechanisms of resistance
• drug-resistant and sensitive isolates of the same
  organism co-exist within the same patient
• Shigella and commensal E.coli in the same patient
  have same drug-resistance profiles
• mutations are not likely to explain these
  observations

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Mechanisms of Drug Resistance

• Reduced permeability
• Prodrug is not activated
• Active efflux (export)
• Alteration of drug target
• Inactivation of a drug
• Bypass inhibited step
• Immunity protein
• Amplification of target
• Sequesteration of drugs

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Origins of antibiotic resistance genes

• Antibiotic resistance genes can be clustered
  similarly to PAI
• have different GC content
• have different codon bias
• Plasmids, transposons, integrons carry antibiotic
  resistance genes
• Housekeeping genes can be modified to function in
  antibiotic resistance
• aminoglycoside acetyl transferases and
  B-lactamases
• Genes horizontally transferred from
  antibiotic-producing microbes
• many antibiotics are of bacterial origins.
  Microbes that synthesize antibiotics are also
  resistant to them

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Origins of antibiotic resistance genescontd

• Mosaic genes
• b-lactamases in Neisseria and Streptococcus have
  mosaic structure
• resistance to mupirocin is due to an altered
  tRNA-isoleu that may have originated in
  eukaryotes
• Resistance by mutation
• endogenous genes mutate. Rate and the role of
  mutagenesis is different in different microbes
• M. tuberculosis
• Frequency of spontaneous mutations 10-6-10-7.
• No compound transposons in Mycobacteria
• No known exogenously acquired plasmids
• Resistance to synthetic drugs can (typically)
  come from mutation
• Mutator phenotypes
• methyl-directed mismatch repair controls fidelity
  of recombination. Inhibits recombination between
  non-identical DNA sequences
• mutations in repair genes makes the organism
  hypermutagenic (100-1,000x increase in mutation
  rates)

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Trade-off of antibiotic resistance

• In the absence of selection, theres a metabolic
  price for expressing resistance genes
• Altered structures of replication machinery, cell
  envelope
• Sometimes have reduced virulence
• Salmonella resistant to 3 antibiotics were
  cleared from mice
• Compensatory mutations

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Mechanisms of resistance gene acquisition

• Transformation
• Conjugation
• Conjugative transposons
• Composite transposons
• Integrons

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Transformation
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Transformation

• Bacteria take up DNA (linear or plasmid) from the
  environment
• Some bacteria are naturally competent
• DNA thats taken up can recombine --gt may lead to
  mosaic genes

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Conjugation
Conjugation takes place in intestines, in biofilms
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Transposons
Transposons can carry antibiotic-resistance
genes An insertion of a transposon also leads
to a mutation An insertion of a transposon into
a genome may also generate a recombination
hot-spot
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Transposons

• Conjugative transposons
• Upon self-excision form a covalently bound
  circular intermediate
• Unlike conjugative plasmids, conjugative
  transposons cannot replicate themselves
• Composite transposons
• Mobile elements that carry multiple antibiotic
  resistance genes
• Integrons. Natures biotech

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• Integrons