5 Cell wall Synthesis Inhibitors and their Mode of Action

5 Cell wall Synthesis Inhibitor Drugs and its Mode of action

Cell wall is a rigid layer of polysaccharides present outside the plasma membrane of the cells of plants, fungi, and bacteria. In the algae and higher plants it consists mainly of cellulose.

• In fungus, cell wall is primarily made up of chitin
• In Bacteria, cell wall is primarily made up of peptidoglycan except in archaebacteria
• Cell wall offers protection to the cell and maintains its structure and shape
• Many drugs target cell wall as cell wall is essential for the survival of infectious pathogens

Cell wall synthesis inhibitors

1. Penicillin: 

• β lactam antibiotics (beta-lactam ring in their structure)
• effective against gram positive bacteria
• Inhibits bacterial cell wall formation by blocking cross linking of the cell wall structure.
• Inhibits transpeptidase enzyme
• Bacteria formed in the presence of beta-lactams lack cell-wall.

Mode of action: Beta-Lactam Antibiotics bind to specific receptors on bacterial cell membrane called Penicillin Binding Proteins (PBPs) thus inhibiting transpeptidase enzyme that catalyzes cross- linking of peptidoglycan chains of the bacterial cell wall. The target bacterium undergo lysis or cell breakage without cell wall.

2. Cephalosporin: 

• β lactam antibiotics but broad spectrum antibiotic
• Broad spectrum antibiotic generally effective against both Gram positive and Gram negative bacteria.
• having 7- aminocephalosporanic acid nucleus

Mode of action: Similar to penicillin

3. Vancomycin

• Vancomycin is a unique glycopeptide structurally unrelated to any currently available antibiotic.
• Narrow spectrum antibiotic which inhibits the second phase of cell wall synthesis
• Effective against Gram positive bacteria

Mode of action

Vancomycin recognizes and binds to the two D-ala residues on the end of the peptide chains. Thus prevent cross linking of cell wall strands by preventing the binding of cross linking enzyme

There is also evidence that vancomycin alters the permeability of the cell membrane and selectively inhibits ribonucleic acid synthesis.

4. Bacitracin

• polypeptide antibiotic derived from B. subtilis
• primarily effective against gram positive bacteria
• Inhibits peptidoglycan strand synthesis

Mode of action

Peptidoglycan monomers - consisting of the sugars NAM and NAG with a pentapeptide coming off the NAM - are synthesized in the cytosol of the bacterium. These monomers are then transported across the cytoplasmic membrane and inserted into the growing peptidoglycan chain by membrane transporters called bactoprenols.

Bacitracin binds to bactoprenol after it inserts the peptidoglycan monomer transported into the growing cell wall. It subsequently prevents the dephosphorylation of the bactoprenol. Bactoprenol molecules that have not lost the second phosphate group cannot assemble new monomers and transport them across the cytoplasmic membrane. As a result, no new monomers are inserted into the growing cell wall.

Without the active dephosphorylated bactoprenol, peptidoglycan synthesis cannot be completed and the cell lyses occurs*

5. Fosfomycin

• Phosphonic acid derivative produced by Streptomyces sps
• Broad spectrum antibiotic effective against both Gram positive and Gram negative bacteria.
• Acts as phosphoenolpyruvate (PEP) analogue inhibiting the enzyme MurA involved in the first committed step of peptidoglycan cell wall biosynthesis

Mode of action:

Fosfomycin is a phosphoenolpyruvate (PEP) analog that irreversibly inhibits of MurA (UDP-N-acetylglucosamine-3-enolpyruvyl transferase), the cytosolic enzyme responsible for the first step in the peptidoglycan biosynthesis pathway that produces UDP-N-acetylmuramic acid. 

MurA is responsible for catalyzing the transfer of  enolpyruvate moiety of phosphoenolpyruvate (PEP) to the 3′-hydroxyl group of UDP-N-acetylglucosamine in the pathway that produces UDP-N-acetylmuramic acid 

References

Castañeda-García, A., Blázquez, J., & Rodríguez-Rojas, A. (2013). Molecular mechanisms and clinical impact of acquired and intrinsic fosfomycin resistance. Antibiotics, 2(2), 217-236.

Zhanel, G. G., Walkty, A. J., & Karlowsky, J. A. (2016). Fosfomycin: a first-line oral therapy for acute uncomplicated cystitis. Canadian Journal of Infectious Diseases and Medical Microbiology, 2016.

http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit2/control/bacresillus.html