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Discovery of penicillin 1929. Sir Alexander Fleming. Accidental mold contamination. Chinese, Egyptians, Europeans used moldy food to treat infections. Bacterial Drug Resistance. Bacterial Resistance. Many bacterial have developed antibiotic resistance.

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bacterial drug resistance
Discovery of penicillin 1929.

Sir Alexander Fleming.

Accidental mold contamination.

Chinese, Egyptians, Europeans used moldy food to treat infections.

Bacterial Drug Resistance
bacterial resistance
Bacterial Resistance
  • Many bacterial have developed antibiotic resistance.
    • 80% of Staphylococcus resistant to penicillin.
    • “Superbugs” resistant to all antibiotics.
    • Multi-drug resistant tuberculosis.
  • Misuse of antibiotics accelerates rates of resistance.
antibiotic examples
Antibiotic Examples
  • b-Lactam antibiotics (e.g., Penicillin):
    • Transpeptidase crosslinks the peptidoglycan net in the cell wall of Gram-positive bacteria.
    • The b-lactam ring mimics a component of the cell wall to which transpeptidase binds, inhibiting the binding of transpeptidase.
    • Bacterium lyse (rupture) because the cell wall is weakened.
  • Disrupters of nucleic acid synthesis prevent bacterial cell division.
    • The antibiotic rifampin interferes with prokaryotic RNA polymerase.
    • Fluoroquinolones inhibit DNA gyrase.
  • Disrupters of protein synthesis:
    • Aminoglycosides inhibit nucleic acid or protein synthesis in bacteria.
    • L-shaped molecules that fit into pockets of bacterial ribosomal RNA.
    • When they insert themselves into rRNA, they disrupt ribosomal structure.
    • L-shaped pocket is specific to bacteria.
mechanisms of resistance
Mechanisms of Resistance
  • Bacteria either have preexisting resistance to drugs, or they develop resistance.
  • Often resistance to a certain drug from a particular class leads to resistance to all other drugs in that class.
inherent resistance
Inherent Resistance
  • Darwinian evolution:
    • Bacteria that resist an antibiotic's effects are better suited to survive in an environment that contains the antibiotic.
    • Genes that confer resistance are transferred to the bacterial progeny.
  • Bacteria naturally resistant (e.g., Gram-negative bacteria resistant to penicillins).
  • Bacteria may be resistant because
    • They have no mechanism to transport the drug into the cell.
    • they do not contain or rely on the antibiotic’s target process or protein.
acquired resistance
Acquired Resistance
  • Bacteria that don’t begin life resistant to a certain antibiotic can acquire that resistance.
  • Horizontal evolution:
    • Resistance genes pass from a resistant strain to a nonresistant strain, conferring resistance on the latter.
    • Presence of a antibiotic is a selective pressure.
  • Gene transfer mechanisms:
    • Conjugation.
    • Transduction.
    • Transformation.
  • Transmission of resistance genes via plasmid exchange.
  • Resistance spreads much faster than simple mutation and vertical evolution would permit.
transduction and transformation
Transduction and Transformation
  • Transduction: Virus transfers gene.
  • Transformation: DNA released from a bacterium is picked up by a new cell.
mechanisms of resistance1
Mechanisms of Resistance
  • Enzyme-based resistance–break down or modify antibiotic.
  • Ribosomal modifications–methylation of ribosome interferes with antibiotic binding.
  • Protein modifications–mutations leave target protein unrecognizable to antibiotic yet still functional.
  • Metabolic resistance–overcome competitive inhibition by producing excess of metabolite.
  • Effluxing the toxin–pump it out.
enzyme based resistance b lactamase
Enzyme-Based Resistance: b-Lactamase
  • Enzymes can destroy or disable antibiotics.
  • For example, b-lactamase hydrolyzes b-lactam ring of penicillins.
  • Without a b-lactam ring, penicillins ineffective.
enzyme based resistance aminoglycoside disruption
Enzyme-Based Resistance:Aminoglycoside Disruption
  • A bacterial enzyme adds a bulky substituent to the aminoglycoside (such as chloramphenicol).
  • Antibiotic now does not fit into the rRNA pocket, rendering it harmless.
  • We overuse antibiotics and often neglect to complete a full course of antibiotics once it has been prescribed, leading to the spread of antibiotic resistance.
  • Resistance can disappear if there is no selective pressure to maintain resistance.