the cell wall description and the difference between the gram positive and negative bacteria and the structure of peptidoglycan and the biosynthesis of the cell wall (peptidoglycan) in bacteria and the end is with some groups of antibiotics that inhibit the synthesis of peptidoglycan in different ways and targets the bacteria.

1. IN THE NAME OF GOD
Bacterial Biosynthesis and Antibiotics
Presented By: Safa Fallah

2. Content:
Cell Wall
Structure of Peptidoglycan
Patterns of synthesis
Functions of Peptidoglycan
Antibiotics
Inhibiting peptidoglycan synthesis
Source of antibiotics
Bacterial resistance to ANTIMICROBIAL AGENTS

3. The Cell Wall
• Surrounds the entire Bacteria
• Hold the Cell together and offer protection
• Maintain Osmotic Pressure
• Maintain the shape of the Cell
• Play an essential role in Cell Division
• Not present in animal cells, so can target cell wall of bacterial with Antibiotics
• Christan Gram (1884) proved that there are two major groups of Prokaryotes
based on composition of the cell wall
• The strength of the wall is mainly due to Peptidoglycan

5. Peptidoglycan
o Peptido means short peptide and glycan means polysaccharide
o Also known as Murein in an enormous Heteropolymers
o Consist of two Sugar (N-asetylglucosamin and N-asetylmuramic acid)
o Contain several Amino acids (D-glutamic acid, D-Alanine, meso-
diaminopimelic and L-Alanine)
o Forms Around 90%of the dry wight of Gram positive and only 10% of Gram
negative bacteria’s
o This layer is thicker in Gram positive than Gram negative Bacterias
o Outer membrane is absent in gram positive bacteria present in gram
negative bacteria
FUNCTIONS OF PEPTIDOGLYCAN
✓ prevents bacteria from lysis due to turgor
✓ maintains cell shape
✓ protects the cell from extreme environmental conditions

10. Structure of Peptidoglycan
o N-acetylglucoseamin and N-acetylmuramic acid (NAG & NAM) are
connected by a β(1,4)-glycosidic bond
o Each NAM is attached to amino acid chains (which differ from one
bacteria to other)
• In the case of E.coli L-Alanine, D-glutamic acid, meso-diaminopimelic and D-
Alanine (gram negative)
• In the case of Staphylococcus aureus L-Alanine, D-glutamine, L-lysin and D-alanine
with 5-glycin interridge between tetrapeptides (gram positive)

13. BIOSYNTHESIS OF PEPTIDOGLYCAN
o It take place in cytoplasm, inner and outer side of the cytoplasmic membrane
o Complex process involve enzyme reactions
o The Biosynthesis of Bacterial Peptidoglycan is a two stage process
➢ First stage: Formation of disaccharides peptide monomer unit
➢ Second stage: Polymerization reactions accompanied by interactions of newly made peptidoglycan
material into cell wall.

14. Fructose-6-phosphate Glucoseamine-6-p Glucoseamine-1-p N-acetyl-Glucoseamine-1-p
UDP-NAG
UDP-NAG-enol-pyruvate
UDP-NAM
UDP-NAM-L-ala
UDP-NAM-Dipeptide
UDP-NAM-Tripeptide UDP-NAM-Pentapeptide Bactoprenol-pp-NAM-Pentapeptide (lipid1)
Bactoprenol-pp-NAM-NAG-Pentapeptide (lipid 2)
PEPTIDOGLYCAN
GLM
U
GLM S GLM M
UTP
UDP
PEP
MurA or MurZ
NADPH
MurB
MurC
MurD
MurE
MurF Undecaprenyl
MurY
MurG
P
L-Ala
D-Glu
L-lys
D-Ala D-Ala
acetyl CoA CoA
STAGE ONE
STAGE TWO

16. ❑ disrupt essential processes or structures in the bacterial cell.
❑ Damage structure (Presented in bacteria)
❑ Work with immune system
❑ antibiotics are "selectively" toxic to bacteria
❑ either kills the bacterium or slows down bacterial growth.
❑ Bactericidal and bacteriostatic antibiotics
▪ bactericidal antibiotic kills the bacteria
▪ bacteriostatic antibiotics stop bacterial growth without killing them
ANTIBIOTICS
Three main Antibiotic targets in Bacteria:
The cell wall or membranes that surrounds the bacterial cell
The machineries that make the nucleic acids DNA and RNA
The machinery that produce proteins (the ribosome and associated
proteins)

17. Inhibiting peptidoglycan synthesis:
1. The antibiotic cycloserine
• an analog of D-alanine
• interferes with the enzymatic conversion of L-alanine to D-alanine
• in the cytoplasm
2 . Bacitracin
• prevents the dephosphorylation reaction
• in the absence of the monophosphorylated transporter
• the synthesis of the peptidoglycan subunit is stopped.

18. 3 . Vancomycin
• In the final stage of peptidoglycan
• binds to D-alanine
• strongly inhibits transpeptidation (cross-linking).
• Only active against Gram positive bacteria
4 . Beta-lactam antibiotics
• In the wall (penicillin and cephalosporin).
• cytoplasm (fosfomycin, cycloserine)
• in the cytoplasmic membrane (vancomycin and Bacitracin )
• include penicillins, cephalosporins and monobactams
• bind to and inhibit the enzymes involved in the transpeptidation of peptidoglycan
• These antibiotics all have are a 4-membered ring

19. Cell wall
Vancomycin
Cell wall
Penicillin binding protein
β lactam
Active site
of enzyme

20. C NH CH CH C
O
O C N CH
CH3
CH3
COOH
S
Site of penicillinase action.
Breakage of the β lactam ring.
Penicillin
❖ is produced by the fungus Penicillium chrysogenum
❖ have a 5-membered lactam ring
❖ Some penicillins show little activity against Gram-negative bacteria, because they
are not able to penetrate their outer membrane.
STRUCTURE OF PENICILLIN

21. Cephalosporins
❖ obtained from Acromonium mold (fungi)
❖ are also effective against Gram-negative bacteria because they can pass through
this membrane.
❖ They are attached to the enzyme responsible for making peptidoglycan and
prevent its activity.
Tetracyclines
❖ used in the treatment of infections caused by sensitive microorganisms(such as
Gram-positive(Staphylococci,Streptococci) , Gram-negative bacteria,
Chlamydiae, Mycoplasmata, Protozoans. Rickettsiae)
❖ Bind reversibly to bacterial 30S ribosomal
❖ Inhibit protein synthesis
❖ Bacteriostatic

22. Daptomycin
• Causes depolarization of bacterial cell membrane (shift in electric charge distribution,
resulting in less negative charge inside the cell compared to the outside.)
•treat various bacterial infections caused by Gram-positive bacteria
Polymyxin B
• binds
– lipid A
– phospholipids
• disrupts outer membrane, Gram negative bacteria
• toxic to human cells
Daptomycin

23. AMINOGLYCOSIDES
✓ Inhibit bacterial protein synthesis by irreversibly binding to 30S ribosomal unit
•Naturally occurring:
•Streptomycin
•Neomycin
•Kanamycin
•Tobramycin
•Gentamicin
•Semisynthetic derivatives:
•Amikacin (from Kanamycin)
•Netilmicin (from Sisomicin)
Causes mRNA decoding errors
30S Ribosomal Unit
Blockage by
Aminoglycosides

24. SOURCE OF ANTIBIOTICS
 Fungi
 Penicillin, Griseofulvin, Cephalosporin
 Bacteria
 Polymyxin B, Colistin, Bacitracin, Aztreonam.
 Actinomycetes.
 Aminoglycosides, Macrolides, Tetracyclines, Polyenes,
Chloramphenicol

25. Bacterial resistance to ANTIMICROBIAL AGENTS
3 general categories
 Drug does not reach its target
 Drug is not active
 Target is altered

26. References :
➢ Schleifer, K.H., and Kandler(1972), "Peptidoglycan types of bacterial cell walls and their taxonomic
implications". Bact. Rev., 36, 407.
➢ Hélène Barreteau, Andreja Kovač, Audrey Boniface, Matej Sova, Stanislav Gobec, Didier Blanot,
Cytoplasmic steps of peptidoglycan biosynthesis, FEMS Microbiology Reviews, Volume 32, Issue 2,
March 2008, Pages 168- 207, https://doi.org/10.1111/j.1574-6976.2008.00104.x
➢ Bouhss A, Trunkfield AE, Bugg TD, Mengin-Lecreulx D. The biosynthesis of peptidoglycan lipid-linked
intermediates. FEMS Microbiol Rev. 2008 Mar;32(2):208-33. doi: 10.1111/j.1574-6976.2007.00089.x.
Epub 2007 Dec 10. PMID: 18081839.
➢ Nathan C. Antibiotics at the crossroads. Nature. 2004;431:899–902. doi: 10.1038/431899a.
➢ An oldie but a goodie – cell wall biosynthesis as antibiotic target pathway
Author: Tanja Schneider,Hans-Georg Sahl
Publication: International Journal of Medical Microbiology
Publisher: Elsevier
Date: February 2010

27. THANK YOU