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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

Jamming the Ribosome: Three Binding Sites, Three Outcomes

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Once the wall is breached, the next vulnerable machine is the one that builds protein. The 70S ribosome sits as two stacked subunits, the 30S below and the 50S above, with the mRNA message threaded between them. Aminoacyl-tRNA molecules carry amino acids into the A site, the peptide bond forms, and the growing chain slides out through a tunnel in the 50S. That leaves three separate pockets a drug could occupy, and which pocket gets filled decides what happens to the cell.
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The 70S ribosome is built from two subunits, the 50S and the 30S, and each one offers its own drug-binding pockets. Aminoglycosides such as gentamicin bind the 30S subunit at the decoding site of the 16S rRNA. That site is where the ribosome checks each codon against its tRNA, so disturbing it lowers the fidelity of codon-anticodon pairing: incorrect amino acids get inserted, and translocation is blocked as well. The proteins that come out are misfolded and nonfunctional, and because damaged protein piles up and membrane insertion fails, the aminoglycoside is bactericidal.

Tetracyclines also bind the 30S subunit, but at the A site, where they sterically block the incoming aminoacyl-tRNA from docking. Protein synthesis stops, yet the cell is not immediately destroyed, so tetracyclines are typically bacteriostatic. Macrolides such as erythromycin bind the 50S subunit inside the nascent peptide exit tunnel, so the growing polypeptide cannot move out. Synthesis halts here too, and macrolides are generally bacteriostatic.

The pattern holds: the subunit and the exact site decide whether the drug merely stops translation or also drives the cell to make toxic, misfolded products. That is one reason aminoglycosides kill while tetracyclines and macrolides mainly hold growth in check.

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