Bacterial Drug Resistance

1. Discovery of penicillin 1929. Sir Alexander Fleming. Accidental mold contamination. Chinese, Egyptians, Europeans used moldy food to treat infections. Bacterial Drug Resistance

2. 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.

3. Sources of Antibiotics

4. Antibiotic Mechanisms

5. 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.

6. Antibiotic Mechanisms

7. 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.

8. 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.

9. 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.

10. Conjugation • Transmission of resistance genes via plasmid exchange. • Resistance spreads much faster than simple mutation and vertical evolution would permit.

11. Transduction and Transformation • Transduction: Virus transfers gene. • Transformation: DNA released from a bacterium is picked up by a new cell.

12. Examples of Resistance

13. 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.

14. 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.

15. 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.

16. 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.