Vancomycin Vancocin

Structural Formula

Ball-and-Stick Model

Structural Formula

= Oxygen

= Nitrogen

= Carbon

= Hydrogen

= Oxygen

= Chlorine

= Nitrogen

Year of discovery: ca. 1956; Year of introduction: 1958 (as Vancocin by Eli Lilly); Drug category: Glycopeptide antibiotic; Main uses: For the treatment of life-threatening infections by Gram-positive bacteria that are resistant to all other known antibiotics; Related drugs: Teicoplanin (Targocid).

Vancomycin, the first member of the glycopeptide antibiotic class, was isolated from the soil microbe Amycolatopsis orientalis obtained from the jungles of Borneo. Vancomycin was shown to be bacteriocidal towards Gram-positive (but not Gramnegative) bacteria. It was marketed as Vancocin by Lilly and became widely used as the antibiotic of "last resort" once multidrug-resis-tant bacterial strains began to emerge in the 1960s and 1970s. Another widely used drug with a similar spectrum of activity is teicoplanin (Targocid™, Sanofi Aventis), a lipoglyco-peptide that is only available in Europe.

Teicoplanin (Targocid )

The structures of vancomycin and teicoplanin are closely related and feature heptapeptide scaffolds (blue) linked to sugar and amino-sugar moieties (red). Teicoplanin is classified as a lipoglycopeptide because it contains a long hydrophobic acyl chain (green).1 Vancomycin and teicoplanin are currently reserved for the treatment of life-threatening bacterial infections such as the methicillin-resistant Staphylococcus aureus (MRSA). Vancomycin must be administered intravenously, since it is orally inactive. Due to the emergence of vancomycin-resistant, Gram-positive bacterial strains during the past 15 years, restrictions in the clinical use of vancomycin were introduced by the US Centers for Disease Control.

Glycopeptides halt the development of Gram-positive bacteria by inhibiting the biosynthesis of the peptidoglycan layer of the cell wall. Both vancomycin and teicoplanin bind to late-stage peptidoglycan intermediates containing a D-alanyl-D-alanine terminus. This strong binding blocks further elaboration of the growing glycan chain by transglycosidation or transpeptidation. The D-Ala-D-Ala terminus can form five hydrogen bonds with vancomycin (see X-ray image below)2 In vancomycin-resistant strains the peptidoglycan chains have D-alanyl-D-lactate as terminal units. With this modified terminus only four hydrogen bonds are possible and, as a result, there is a 1000-fold decrease in antibiotic potency against the resistant strains.

H,c " D-Ala-D-Ala Five possible hydrogen bonds with Vancomycin

VANCOMYCIN

MlC Ii D-Aläi-Lac Four possible hydrogen bonds with Vancomycin

H,c " D-Ala-D-Ala Five possible hydrogen bonds with Vancomycin

VANCOMYCIN

N-Acetyl-D-Lys-D-Ala-D-Ala

1. Chem. Rev. 2005, 105, 425-448; 2. Protein Data Bank 2001, (http://www.pdb.orQ/> (1FVM); Refs. p. 175

N-Acetyl-D-Lys-D-Ala-D-Ala

1. Chem. Rev. 2005, 105, 425-448; 2. Protein Data Bank 2001, (http://www.pdb.orQ/> (1FVM); Refs. p. 175

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