Bacterial Drug Resistance Discovery of penicillin –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.