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.