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How Antibiotics Kill Bacteria and Why Resistance Develops

1Bacterial Targets: What Makes a Good Antibiotic Target2How Major Antibiotic Classes Kill Bacteria3Genetic Origins of Resistance: Mutation and Horizontal Gene Transfer4Biochemical Mechanisms of Resistance5Multidrug Resistance, Co-selection, and Clinical Consequences
How Major Antibiotic Classes Kill Bacteria

Cutting the Wall: Beta-Lactams and Glycopeptides

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Peptidoglycan is a mesh of sugar strands held together by short peptide bridges, and the enzyme that welds those bridges is the penicillin-binding protein, or PBP. Watch the PBP reach for a peptide stem to close a cross-link. A beta-lactam slips into the enzyme's active site and forms a stable covalent bond with its serine, so the PBP is locked and that bridge never closes.
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Peptidoglycan is a mesh of glycan strands cross-linked by short peptides, and building it depends on penicillin-binding proteins (PBPs), the transpeptidases that form those peptide cross-bridges. Beta-lactams, including penicillins and cephalosporins, are structural analogs of the terminal D-alanyl-D-alanine of the peptide stem. They acylate the active-site serine of the PBP and form a stable covalent penicilloyl-enzyme complex, so the cross-linking reaction stops. Glycopeptides such as vancomycin work one step earlier: they bind the D-Ala-D-Ala terminus itself by hydrogen bonding and physically block the transpeptidase and transglycosylase from reaching the substrate.

Either way, the wall loses its mechanical strength. Because the bacterial cytoplasm is hypertonic relative to the surrounding medium, water enters and the internal pressure rises. A wall that cannot keep pace with growth and division ruptures, and the cell lyses. That is why beta-lactams and glycopeptides are bactericidal against susceptible, actively growing bacteria: the drug does not simply stop a reaction, it removes the structure that resists osmotic pressure.

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