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Antibiotics That Inhibit Bacterial Peptidoglycan Synthesis: How They Work

  • Author: Gary Kaiser 1
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Biology Department, The Community College of Baltimore County, Catonsville Campus, Baltimore, MD, 21228
  • Citation: Gary Kaiser. 2013. Antibiotics that inhibit bacterial peptidoglycan synthesis: how they work.
  • Publication Date : December 2013
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Summary



With relatively few exceptions, members of the domain Bacteria possess a cell wall composed of a semi-rigid, tight-knit molecular complex called peptidoglycan that enables the bacterium to resist osmotic lysis. Many commonly used antibiotics work by inhibiting peptidoglycan synthesis, resulting in bacterial lysis. These animations illustrate the mechanisms by which several different antibiotics inhibit peptidoglycan synthesis in a Gram-positive bacterium.



Introduction




To synthesize new peptidoglycan during bacterial replication and growth, enzymes called autolysins break the glycosidic bonds between the peptidoglycan monomers at the point of growth along the existing cell wall. In addition, there are autolysins that break the peptide cross-bridges that link the rows and layers of glycan strands together. New peptidoglycan monomers are synthesized in the cytosol of the bacterium as they attach to a membrane carrier molecule called bactoprenol. The bactoprenols transport the peptidoglycan monomers across the cytoplasmic membrane and work with enzymes called transglycosylases to insert the monomers into the existing cell wall. As the new peptidoglycan monomers are inserted, transpeptidase enzymes (also known as penicillin-binding proteins) reform the peptide cross-links between the rows and layers of peptidoglycan making the cell wall strong (1).



Penicillins and cephalosporins, as well as other beta-lactam antibiotics, mimic the D-alanyl-D-alanine (D-Ala-D-Ala) groups found at the terminus of the pentapeptide in most newly synthesized peptidoglycan monomers. Binding of the drug to the transpeptidase ties up the enzyme and prevents it from reforming the peptide cross-links between the rows and layers of peptidoglycan in the cell wall as new peptidoglycan monomers are added during bacterial cell growth. In addition, these antibiotics appear to interfere with the bacterial controls that keep autolysins in check. Collectively, this results in degradation of the peptidoglycan and osmotic lysis of the bacterium (2).



Glycopeptides, such as vancomycin, and the lipoglycopeptide teichoplanin bind directly to the D-Ala-D-Ala portion of the pentapeptides of the peptidoglycan monomers and block the formation of the peptide cross-links by the transpeptidase enzymes. As a result of steric hindrance (not shown in this animation), vancomycin may also interfere with the formation of the glycosidic bonds between the sugars of the peptidoglycan monomers and those in the existing cell wall (2). Collectively, this results in a weak cell wall and subsequent osmotic lysis of the bacterium.



The antibiotic bacitracin, on the other hand, binds to the transporter protein bactoprenol after it inserts the peptidoglycan monomer it is transporting across the cytoplasmic membrane into the growing cell wall. Binding of the drug 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 (2). As a result, no new monomers are inserted into the growing cell wall. As the autolysins continue to break the peptide cross-links and new cross-links fail to form, the bacterium bursts from osmotic lysis.



Method




Adobe Flash Professional CS5.5 was used in constructing this animation. Illustrations were drawn using Adobe Illustrator CS5.1 and imported into Adobe Flash Professional CS5.5.



Discussion




Many commonly used antibiotics work by inhibiting peptidoglycan synthesis, resulting in bacterial lysis. These animations illustrate the mechanisms by which several  different antibiotics inhibit peptidoglycan synthesis in a Gram-positive bacterium.



Animation 1




Penicillin inhibiting the synthesis of peptidoglycan in a Gram-positive bacterium by binding to transpeptidases enzymes.



Slide 1 shows a labeled representation of a Gram-positive cell wall.



Slides 2 and 3 illustrate how transpeptidases normally form the peptide cross-links between the chains of peptidoglycan. One amino acid is lost from the newly inserted monomer during this process, changing it from a pentapeptide to a tetrapeptide.



In slides 4 and 5, penicillin molecules are shown binding to transpeptidases and blocking the formation of the peptide cross-links between the newly inserted monomers and the existing peptidoglycan cell wall.



In slides 6 and 7, the bacterium is shown undergoing osmotic lysis as the autolysins continue to degrade the cell wall.



Animation 2




Vancomycin inhibiting the synthesis of peptidoglycan in a Gram-positive bacterium by binding directly to the pentapeptide of the peptidoglycan monomers.



Slide 1 shows a labeled representation of a Gram-positive cell wall.



Slides 2 and 3 illustrate how transpeptidases normally form the peptide cross-links between the chains of peptidoglycan. One amino acid is lost from the newly  inserted monomer during this process, changing it from a pentapeptide to a tetrapeptide.



In slides 4 and 5, vancomycin is shown binding directly to the pentapeptide of the newly transported peptidoglycan monomers and blocking the formation of the peptide cross-links between these monomers and the existing peptidoglycan by transpeptidases.



In slides 6 and 7, the bacterium is shown undergoing osmotic lysis as the autolysins continue to degrade the cell wall.



Animation 3




Bacitracin inhibiting the synthesis of peptidoglycan in a Gram-positive bacterium by binding to the membrane transporter bactoprenol.



Slide 1 shows a labeled representation of a Gram-positive cell wall.



In slides 2 and 3, peptidoglycan monomers are shown being synthesized in the cytosol as the NAM-pentapeptide attaches to the carrier protein bactoprenol. The bactoprenol subsequently transports the monomers across the cytoplasmic membrane and inserts them into the "gap" provided by the autolysins.



Slides 4 and 5 illustrate how bactoprenol must lose one of its two phosphate groups before it can again help assemble and transport peptidoglycan monomers across the cytoplasmic membrane.



In slides 6 and 7, bacitracin is shown binding to bactoprenol after it inserts the peptidoglycan monomer it is transporting into the growing cell wall. The bacitracin subsequently prevents the dephosphorylation of the bactoprenol and blocks bactoprenol from transporting further peptidoglycan monomers across the membrane.



In slides 8 and 9, the bacterium is shown undergoing osmotic lysis as the autolysins continue to degrade the cell wall.



References



1. Madigan MT, Martinko JM, Stahl DA, Clark DP. 2012. Brock Biology of Microorganisms, 13th ed., p. 58-60; 122-123.  Pearson Education, Inc. Publishing, San Francisco, CA.



2. Van Bambeke F, Lambert DM, Mingeot-Leclercq M, Tulkens PM. 2004. Antibiotics that act on the cell wall, p. 1717-1720. In Cohen, J. and W. G.  Powderly (ed.), Infectious Diseases, 2nd ed. Mosby Publishing, London, UK.

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