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
•
b-Lactam antibiotics (e.g., Penicillin):
– Transpeptidase crosslinks the peptidoglycan net in the cell wall of Grampositive 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.
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., Gramnegative 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:
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
• 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.