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.

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.

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 doesn’t show cross-resistance with beta-lactams, bacitracin or cyclocerin.

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.

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.

R

O

NH

O

H CH3

O

O

O

H CH3

R

O

NH

HN

H CH3

O

O

H CH3

O

C-Terminus of D-Ala-D-Ala peptide

C-Terminus of D-Ala-D-Lactate peptide

Teicopanin

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.

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.

Bacitracin

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.

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.

Polymyxin B

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 α,γ-diaminobutyric acid, and a nine-carbon-fatty acid.

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.

Colistin

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.

Gramicidine

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.

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.

Mechanism of Action

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

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.

There are two types of ionophores:

1) Those which make a hole in the cell membrane which permits the ions to move upon gradient of concentration: Gramicidin and Tyrotricin.

2) 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.

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.

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).

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+.

Valinomycin

Tyrocidin

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.