Inhibition of cell wall synthesis represents a fundamental strategy in combating bacterial infections. This process targets a unique, protective structure found in most bacteria, which is absent in human cells. By disrupting this outer layer, bacterial survival is compromised without harming host cells. Understanding this process provides insight into how many common antibacterial medications achieve their effects.
Bacterial Cell Wall Essentials
Bacteria possess a distinct outer layer, the cell wall, which provides structural support and protection. This wall is primarily composed of peptidoglycan, a large polymer forming a mesh-like sacculus around the bacterial cytoplasmic membrane. Peptidoglycan derives its name from its two main components: glycan strands of repeating disaccharide units and short peptide chains, typically two to five amino acid residues long. These glycan strands consist of alternating N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) units linked by β-1,4 glycosidic bonds.
The peptidoglycan layer is crucial for bacterial survival. It maintains cell shape and protects against osmotic lysis, where cells burst due to excessive water intake. Peptidoglycan synthesis is a complex, multi-step process. It begins with monomeric precursors forming inside the bacterial cytoplasm. These precursors are then transported to the periplasm—the space between inner and outer membranes in some bacteria—where they are polymerized to form the functional peptidoglycan sacculus.
How Cell Wall Synthesis Is Disrupted
Disrupting bacterial cell wall synthesis involves targeting specific steps in its construction pathway. One point of attack is the initial formation of peptidoglycan precursors within the cytoplasm. Enzymes synthesizing these building blocks can be inhibited, preventing the bacterium from starting construction. For instance, the conversion of L-alanine to D-alanine, a component of the muramyl pentapeptide precursor, or the subsequent assembly of D-alanyl-D-alanine, can be blocked.
Once precursors are formed, they must be transported across the bacterial membrane to the site of cell wall assembly. This transport relies on specific lipid carriers. Interfering with their function halts the delivery of building blocks. Without proper transport, precursors accumulate inside the cell, unable to be incorporated into the growing cell wall.
The final stages of cell wall assembly involve the polymerization of glycan strands and their cross-linking by peptide bridges. Penicillin-binding proteins (PBPs) play a role in these processes, performing both transglycosylation (glycan chain elongation) and transpeptidation (cross-linking of peptide chains) reactions. Inhibitors can bind to these PBPs, preventing them from forming the strong, cross-linked peptidoglycan mesh. This leads to a weakened cell wall that cannot withstand internal osmotic pressure, causing the bacterium to rupture and die.
Major Antibiotic Classes Targeting Cell Walls
Several major classes of antibiotics specifically target bacterial cell wall synthesis, each with a distinct mechanism of action.
Beta-lactam Antibiotics
Beta-lactam antibiotics, including penicillins, cephalosporins, carbapenems, and monobactams, work by irreversibly binding to and inhibiting penicillin-binding proteins (PBPs). These bacterial enzymes are responsible for the final transpeptidation (cross-linking) step in peptidoglycan synthesis. Blocking PBP activity prevents stable cell wall formation, leading to bacterial lysis.
Glycopeptide Antibiotics
Glycopeptide antibiotics, such as vancomycin, bind to the D-Ala-D-Ala terminus of peptidoglycan precursors. This physically obstructs transpeptidation enzymes (PBPs) from accessing their substrate, preventing the cross-linking of peptidoglycan strands. This distinct mechanism makes glycopeptides effective against beta-lactam-resistant bacteria.
Bacitracin
Bacitracin interferes with the recycling of undecaprenyl pyrophosphate, a lipid carrier molecule responsible for transporting peptidoglycan precursors across the bacterial membrane. By preventing its dephosphorylation, bacitracin halts the transport of new building blocks to the growing cell wall, leading to a depletion of available precursors at the synthesis site.
Fosfomycin
Fosfomycin targets an early step in peptidoglycan synthesis within the cytoplasm. This antibiotic inhibits the enzyme MurA, which catalyzes the first committed step in the synthesis of N-acetylmuramic acid, a key component of the peptidoglycan backbone. Blocking MurA prevents the formation of the initial peptidoglycan precursor.
Bacterial Defenses Against Cell Wall Inhibitors
Bacteria have evolved various mechanisms to defend themselves against antibiotics that target their cell walls.
Enzymatic Degradation
One common strategy is enzymatic degradation of the antibiotic. Many bacteria produce beta-lactamase enzymes, which chemically break down the beta-lactam ring structure of antibiotics like penicillin, rendering them inactive before they reach their PBP targets. This enzymatic inactivation is a widespread cause of resistance to this antibiotic class.
Target Alteration
Another defense mechanism involves altering the antibiotic’s target. Bacteria can modify their penicillin-binding proteins (PBPs) so that beta-lactam antibiotics no longer bind effectively. Similarly, some bacteria can alter the D-Ala-D-Ala terminus of their peptidoglycan precursors to D-Ala-D-Lac, reducing the binding affinity of glycopeptide antibiotics like vancomycin. These structural changes prevent the antibiotics from interacting with their intended targets.
Efflux Pumps
Some bacteria also employ efflux pumps, specialized protein channels in their cell membranes. These pumps actively transport antibiotic molecules out of the bacterial cell, reducing the intracellular concentration of the drug. By expelling cell wall inhibitors, bacteria can maintain a sub-lethal concentration of the antibiotic inside.