Bacterial Drug Resistance
• Discovery of penicillin 1929.– Sir Alexander Fleming. – Accidental mold contamination.
• Chinese, Egyptians, Europeans used moldy food to treat infections.
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.
Sources of Antibiotics
Antibiotic Mechanisms
Antibiotic Examples• -Lactam antibiotics (e.g., Penicillin):
– Transpeptidase crosslinks the peptidoglycan net in the cell wall of Gram-positive bacteria.
– The -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.
Antibiotic Mechanisms
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• 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
• 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.
Conjugation
• Transmission of resistance genes via plasmid exchange.
• Resistance spreads much faster than simple mutation and vertical evolution would permit.
Transduction and Transformation
• Transduction: Virus transfers gene.
• Transformation: DNA released from a bacterium is picked up by a new cell.
Examples of Resistance
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: -Lactamase
• Enzymes can destroy or disable antibiotics. • For example, -lactamase hydrolyzes -lactam ring of penicillins.• Without a -lactam ring, penicillins ineffective.
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.
Conclusion
• 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.
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