Glycopeptide and Peptide Antibiotics

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Glycopeptide and Peptide Antibiotics
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Glycopeptide Antibiotics

• Their structure is comprised of a polycyclic,
  cross-linked
• array amino acids.
• These amino acids are mostly aromatic, uncommon
  and with D-stereochemistry.
• The polycyclic structure may be glycosylated by
  amino and neutral sugars.
• They are water-soluble polar antibiotics, acidic,
  basic or zwitterionic and are not orally
  absorbed.
• Vancomycin, Teicoplanin are prototypes of this
  class of antibiotics.

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Spectrum of Antibacterial Activity

• Their antimicrobial spectrum is almost G()
  aerobic and anaerobic bacteria.
• They are valuable for treating infections caused
  by G() bacteria, especially staphylococci that
  are resistant to other antibiotics.
• Vancomycin is important for treating
  antibiotic-induced enterocolitis associated with
  C.difficle.

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Vancomycin

• Aglycon Aglucovancomycin with resorcinol derived
  amino acids. It has ¾ of the potency of
  vancomycin.
• Glycone Glucose, Vancosamine.
• 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.
• It doesnt show cross-resistance with
  beta-lactams, bacitracin or cyclocerin.

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Spectrum of Activity

• Isolated from Amycolatopsis orientalis in 1956.
• Effective against G() streptococci,
  staphylococci, and pneumococci.
• Ineffective against G(-) bacteria, except for
  Neisseria spp.
• In G() endocarditis caused by MRSA.
• Since it is not absorbed from GI it is used for
  treating antibiotic-induced enterocolitis
  associated with C.difficle.

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Mechanism of Bacterial Resistace

• Changing the D-Ala-D-Ala unite of the
  peptidoglycane to D-Ala-D-Lactate which cannot be
  bond to vancomycin.

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Teicopanin
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Teicoplann

• A mixture of 5 structurally close antibiotics
  differing only in the acetyl group of the
  acylglucosamine moiety.
• Antibacterial effect and mechanism similar to
  vancomycin, but more lipid-soluble.
• High protein binding and slow release of the
  tissues One dose a day.
• Effective against G() streptococci,
  staphylococci, enterococci, clostridiums,
  corinebacteriums and propionibacterium acnea.
• Ineffective against G(-) bacteria, except for
  Neisseria spp.

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Peptide Antibiotics

• They are a large diverse class of natural
  products.
• Some contain only amino acids joined by amide
  bonds, whereas others contain nonamino acid
  constituents joined the in ways other than
  conventional peptide linkage.
• The amino acids range from those commonly found
  in proteins to uncommon ones, with highly
  modified structures.
• The peptide array may be linear or cyclic or
  various combinations thereof.

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Bacitracin
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Bacitracin

• Isolated from Bacillus subtilis in the lesions of
  the broken leg of a 7-years old girl, Margaret
  Tracy.
• Effective against G() bacteria.
• Locally or IM against resistant staphs, orally
  for treating enteropathogen diarrhoea, especially
  against Clostridium difficle.
• Disinfecting the gut before an operation.

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Mechanism of Antimicrobial Activity of Bacitracin

• It forms chelates with heavy metals. EDTA
  deactivates it, So
• Divalent ions such as Zn2 are necessary for the
  antimicrobial action of Bacitracin.
• It inhibits the biosynthesis of peptidoglycan of
  the bacterial cell wall by inhibition of
  dephosphorylation of phospholipid.

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Polymyxin B
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Polymyxin B

• 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.
• It is characterized by a cyclic heptapeptide with
  several units of a,?-diaminobutyric acid, and a
  nine-carbon-fatty acid.

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Clinical application and Mechanism of
Antibacterial Action

• It complex with membrane phospholipids and
  disrupt cell membranes similar to cationic
  detergents.
• Bactericidal but restricted to G(-) bacteria.
• It is used locally for the local infections of
  wounds and in burns along with a G()
  antibacterial, bacitracin.
• It is used orally for the treatment of GI
  infections such as pseudomona induced entritis or
  shigellosis.
• IM or intrathecal injection for systemic
  infections.

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Colistin
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Colistin

• It was isolated in 1950 from Aerobacillus
  colistinus.
• Spectrum of antimicrobial activity and mechanism
  of action similar to polymyxin.
• Active against Aerobacter, Bordetella,
  Eschershia, Klebsiella, Pseudomona and Shigella
  spp.
• Structurally different from poymyxin in the
  replacement of a D- Leucin for a D-Phenylalanine.

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Gramicidine
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Gramicidine

• It is obtained by extraction from tyrothricin, a
  mixture of two polypeptides isolated from
  Bacillus brevis.
• Tyrothricin is consisted of gramicidins and
  tyrocidins.
• Gramicidin is a mixture of A1, A2, A3, B1, B2 and
  C.
• Gramicidin is more effective antibacterial in
  tyrothricin mixture.
• It acts as an ionophore in the bacterial cell
  wall and makes a hole in it Bactericidal.
• Active against G() bacteria.

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Spectrum of activity

• Active against G() bacteria.
• It is used only locally, systemic administration
  causes erythrocyte membrane lysis.
• It cannot be administered on open wounds.

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Mechanism of Action

• It acts as an ionophore in the bacterial cell
  wall and makes a hole in it Bactericidal.

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Ionophores

• Ionophores are agents that enter the cell
  membrane and change its permeability.
• They make the ions move inward and outward of the
  cell membrane, so the ion concentrations will
  become equal in both sides.

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• There are two types of ionophores
• Those which make a hole in the cell membrane
  which permits the ions to move upon gradient of
  concentration Gramicidin and Tyrotricin.
• 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.

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Gramicidin as an ionophore

• 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.
• 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.
• A single gramicidin channel can allow the
  transport of up to 107 K ions per second.

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• 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).

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Carrier Ionophores

• Carrier ionophores are specific for particular
  ions.
• Valinomycin will transport K but not Na or Li.
• It forms an octahedral complex with six
  carbonyl-group oxygen atoms acting as ligands.
• The resulting complex has a hydrophobic exterior,
  which allows the complex to diffuse through the
  membrane.
• 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.

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Valinomycin
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Tyrocidin
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Tyrocidin

• It is extracted from tyrothricin as a mixture of
  tyrocidin A, B, C, D.
• It acts as an ionophore in the bacterial cell
  wall and makes a hole in it Bactericidal.
• Active against G() bacteria.
• It is used only locally, systemic administration
  causes erythrocyte membrane lysis.
• It cannot be administered on open wounds.