Antibacterial Agents- Cell Wall synthesis inhibitors, Mechanism of action and resistance
Inhibitors of Bacterial Cell Wall Synthesis
These agents target the bacterial cell wall, an essential structure that protects bacteria and is different from human cells, allowing for selective toxicity .The main target is the peptidoglycan layer.
- Mechanism of Action:
- These drugs interfere with the formation or integrity of the peptidoglycan layer
- Damage to the cell wall leads to cell lysis
- They are generally bactericidal, meaning they kill bacteria irreversibly.
- Types of Inhibitors:
- β-Lactam Antibiotics:
- Mechanism of Action: They contain a β-lactam ring and irreversibly bind to penicillin-binding proteins (PBPs), which are enzymes responsible for the final cross-linking of peptidoglycan chains This inhibits peptidoglycan synthesis Their bactericidal effect is primarily seen during bacterial cell division.
- Examples: Penicillins, Cephalosporins, Carbapenems, and Monobactams Penicillins can be natural (e.g., Penicillin G, Penicillin V) or semisynthetic (e.g., Amoxicillin, Oxacillin) Spectrum varies from narrow to broad depending on the specific drug and generation
- Resistance Mechanisms:
- Production of β-lactamases: Enzymes that hydrolyse the β-lactam ring, inactivating the .Over 200 different β-lactamases are known.
- Alteration in PBPs: Changes in the structure of the target binding proteins reduce the antibiotic's ability to bind effectively, as seen in Methicillin-Resistant Staphylococcus aureus (MRSA)
- Glycopeptides:
- Mechanism of Action: They prevent peptidoglycan synthesis by binding to the D-alanyl-D-alanine precursors which blocks the incorporation of subunits into the cell wall.
- Examples: Vancomycin and Teicoplanin
- Spectrum: Effective primarily against Gram-positive bacteria including those resistant to β-lactams like MRSA. They are generally inactive against Gram-negative bacteria because they cannot penetrate the outer membrane.
- Resistance Mechanisms: Can occur through changes in the D-alanyl-D-alanine target site
- Fosfomycin:
- Mechanism of Action: Blocks murein biosynthesis.
- Spectrum: Broad spectrum, bactericidal.
- Resistance: Resistance develops rapidly It is often used in combination therapy
- Bacitracin:
- Mechanism of Action: Interferes with the recycling of the lipid carrier needed for peptidoglycan synthesis [Mechanisms not explicitly detailed in new sources, but identified as a cell wall inhibitor:
- Spectrum: Primarily active against Gram-positive bacteria.
- Usage and Adverse Effects: Due to nephrotoxicity when used systemically, it is mainly used topically for skin infections.