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Glycopeptide And Peptide Antibiotics


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Glycopeptide And Peptide Antibiotics

  1. 1. Glycopeptide and Peptide Antibiotics dr shabeel pn
  2. 2. Glycopeptide Antibiotics <ul><li>Their structure is comprised of a polycyclic, cross-linked </li></ul><ul><li>array amino acids. </li></ul><ul><li>These amino acids are mostly aromatic, uncommon and with D-stereochemistry. </li></ul><ul><li>The polycyclic structure may be glycosylated by amino and neutral sugars. </li></ul><ul><li>They are water-soluble polar antibiotics, acidic, basic or zwitterionic and are not orally absorbed. </li></ul><ul><li>Vancomycin, Teicoplanin are prototypes of this class of antibiotics. </li></ul>
  3. 4. Spectrum of Antibacterial Activity <ul><li>Their antimicrobial spectrum is almost G(+) aerobic and anaerobic bacteria. </li></ul><ul><li>They are valuable for treating infections caused by G(+) bacteria, especially staphylococci that are resistant to other antibiotics. </li></ul><ul><li>Vancomycin is important for treating antibiotic-induced enterocolitis associated with C.difficle. </li></ul>
  4. 6. Vancomycin <ul><li>Aglycon: Aglucovancomycin with resorcinol derived amino acids. It has ¾ of the potency of vancomycin. </li></ul><ul><li>Glycone: Glucose, Vancosamine. </li></ul><ul><li>Forms hydrogen bonding with D-Alanyl-D-Alanine portion of UDP-N-acetylmuramyl peptide and inhibits cross-linking of peptidoglycane. This causes the destruction of the bacterial cell wall. </li></ul><ul><li>It doesn’t show cross-resistance with beta-lactams, bacitracin or cyclocerin. </li></ul>
  5. 8. Spectrum of Activity <ul><li>Isolated from Amycolatopsis orientalis in 1956. </li></ul><ul><li>Effective against G(+) streptococci, staphylococci, and pneumococci. </li></ul><ul><li>Ineffective against G(-) bacteria, except for Neisseria spp. </li></ul><ul><li>In G(+) endocarditis caused by MRSA. </li></ul><ul><li>Since it is not absorbed from GI it is used for treating antibiotic-induced enterocolitis associated with C.difficle. </li></ul>
  6. 9. Mechanism of Bacterial Resistace <ul><li>Changing the D-Ala-D-Ala unite of the peptidoglycane to D-Ala-D-Lactate which cannot be bond to vancomycin. </li></ul>
  7. 11. Teicopanin
  8. 12. Teicoplann <ul><li>A mixture of 5 structurally close antibiotics differing only in the acetyl group of the acylglucosamine moiety. </li></ul><ul><li>Antibacterial effect and mechanism similar to vancomycin, but more lipid-soluble. </li></ul><ul><li>High protein binding and slow release of the tissues: One dose a day . </li></ul><ul><li>Effective against G(+) streptococci, staphylococci, enterococci, clostridiums, corinebacteriums and propionibacterium acnea. </li></ul><ul><li>Ineffective against G(-) bacteria, except for Neisseria spp. </li></ul>
  9. 13. Peptide Antibiotics <ul><li>They are a large diverse class of natural products. </li></ul><ul><li>Some contain only amino acids joined by amide bonds, whereas others contain nonamino acid constituents joined the in ways other than conventional peptide linkage. </li></ul><ul><li>The amino acids range from those commonly found in proteins to uncommon ones, with highly modified structures. </li></ul><ul><li>The peptide array may be linear or cyclic or various combinations thereof. </li></ul>
  10. 14. Bacitracin
  11. 15. Bacitracin <ul><li>Isolated from Bacillus subtilis in the lesions of the broken leg of a 7-years old girl, Margaret Tracy. </li></ul><ul><li>Effective against G(+) bacteria. </li></ul><ul><li>Locally or IM against resistant staphs, orally for treating enteropathogen diarrhoea, especially against Clostridium difficle. </li></ul><ul><li>Disinfecting the gut before an operation. </li></ul>
  12. 16. Mechanism of Antimicrobial Activity of Bacitracin <ul><li>It forms chelates with heavy metals. EDTA deactivates it, So: </li></ul><ul><li>Divalent ions such as Zn 2+ are necessary for the antimicrobial action of Bacitracin. </li></ul><ul><li>It inhibits the biosynthesis of peptidoglycan of the bacterial cell wall by inhibition of dephosphorylation of phospholipid. </li></ul>
  13. 18. Polymyxin B
  14. 19. Polymyxin B <ul><li>It is isolated from Bacillus polymyxa in 1947 in a mixture along with polymyxin A, B1. B2, C, D1, D2, M, Colistin A, Colistin B, Circulin A,B. </li></ul><ul><li>It is characterized by a cyclic heptapeptide with several units of α,γ-diaminobutyric acid, and a nine-carbon-fatty acid. </li></ul>
  15. 22. Clinical application and Mechanism of Antibacterial Action <ul><li>It complex with membrane phospholipids and disrupt cell membranes similar to cationic detergents. </li></ul><ul><li>Bactericidal but restricted to G(-) bacteria. </li></ul><ul><li>It is used locally for the local infections of wounds and in burns along with a G(+) antibacterial, bacitracin. </li></ul><ul><li>It is used orally for the treatment of GI infections such as pseudomona induced entritis or shigellosis. </li></ul><ul><li>IM or intrathecal injection for systemic infections. </li></ul>
  16. 24. Colistin
  17. 25. Colistin <ul><li>It was isolated in 1950 from Aerobacillus colistinus . </li></ul><ul><li>Spectrum of antimicrobial activity and mechanism of action similar to polymyxin. </li></ul><ul><li>Active against Aerobacter, Bordetella, Eschershia, Klebsiella, Pseudomona and Shigella spp. </li></ul><ul><li>Structurally different from poymyxin in the replacement of a D- Leucin for a D-Phenylalanine. </li></ul>
  18. 26. Gramicidine
  19. 27. Gramicidine <ul><li>It is obtained by extraction from tyrothricin, a mixture of two polypeptides isolated from Bacillus brevis . </li></ul><ul><li>Tyrothricin is consisted of gramicidins and tyrocidins. </li></ul><ul><li>Gramicidin is a mixture of A1, A2, A3, B1, B2 and C. </li></ul><ul><li>Gramicidin is more effective antibacterial in tyrothricin mixture. </li></ul><ul><li>It acts as an ionophore in the bacterial cell wall and makes a hole in it: Bactericidal. </li></ul><ul><li>Active against G(+) bacteria. </li></ul>
  20. 28. Spectrum of activity <ul><li>Active against G(+) bacteria. </li></ul><ul><li>It is used only locally, systemic administration causes erythrocyte membrane lysis. </li></ul><ul><li>It cannot be administered on open wounds. </li></ul>
  21. 29. Mechanism of Action <ul><li>It acts as an ionophore in the bacterial cell wall and makes a hole in it: Bactericidal. </li></ul>
  22. 30. Ionophores <ul><li>Ionophores are agents that enter the cell membrane and change its permeability. </li></ul><ul><li>They make the ions move inward and outward of the cell membrane, so the ion concentrations will become equal in both sides. </li></ul>
  23. 31. <ul><li>There are two types of ionophores: </li></ul><ul><li>Those which make a hole in the cell membrane which permits the ions to move upon gradient of concentration: Gramicidin and Tyrotricin. </li></ul><ul><li>Those which carry cations from one side to the other side of the cell membrane: Valinomycin and synthetic molecules such as crown ethers and cryptates. </li></ul>
  24. 32. Gramicidin as an ionophore <ul><li>Two molecules of gramicidin make a channel in the bacterial cell membrane, N- terminals meet in the middle of the membrane and C-terminals are outside it. </li></ul><ul><li>Each gramicidin molecule is in the form of a left-handed helix, which results in the polar groups lining the interior of the channel. This facilitates the transfer of polar ions through the channel. </li></ul><ul><li>A single gramicidin channel can allow the transport of up to 10 7 K + ions per second. </li></ul>
  25. 34. <ul><li>Ion channel of the gramicidin A channel. The channel is represented by a surface that is color-coded according to the lipophilic potential (blue: hydrophilic, red: lipophilic). </li></ul>
  26. 35. Carrier Ionophores <ul><li>Carrier ionophores are specific for particular ions. </li></ul><ul><li>Valinomycin will transport K + but not Na + or Li + . </li></ul><ul><li>It forms an octahedral complex with six carbonyl-group oxygen atoms acting as ligands. </li></ul><ul><li>The resulting complex has a hydrophobic exterior, which allows the complex to diffuse through the membrane. </li></ul><ul><li>The rigid nature of the molecule coupled with its size makes the binding site of it too large to form complexes with Na + or Li + . </li></ul>
  27. 37. Valinomycin
  28. 38. Tyrocidin
  29. 39. Tyrocidin <ul><li>It is extracted from tyrothricin as a mixture of tyrocidin A, B, C, D. </li></ul><ul><li>It acts as an ionophore in the bacterial cell wall and makes a hole in it: Bactericidal. </li></ul><ul><li>Active against G(+) bacteria. </li></ul><ul><li>It is used only locally, systemic administration causes erythrocyte membrane lysis. </li></ul><ul><li>It cannot be administered on open wounds. </li></ul>