Patrick: An Introduction to Medicinal Chemistry 5e Chapter 21 CYCLOSERINE BACITRACIN VANCOMYCIN VANCOMYCIN ANALOGUES modified

. . . 1. Cell Wall Biosynthesis Cytoplasm Cell membrane Growing cell wall . Crosslinking b-Lactams Vancomycin . Gly . Transglycosidation NAG Carrier lipid Bacitracin L-Ala D-Glu L-Lys NAM Bullet point order changed Crosslinking Modified wrt glycine chains L-Ala D-Ala D-Ala- D-Ala Cycloserine Amino acid Building block partially constructed in cytoplasm Transported across cell membrane and completed Constructed from 2 sugars (NAM, NAG) and a peptide chain Linked to growing cell wall by enzyme (transglycosidation) Final crosslinking reaction catalysed by transpeptidase enzymes

. 2. D-Cycloserine Natural product produced by Streptomyces garyphalus Cytoplasm Cell membrane NAM Carrier lipid L-Ala D-Glu L-Lys D-Ala D-Ala- D-Ala Amino acid NAG Gly . Transglycosidation Vancomycin Growing cell wall Crosslinking b-Lactams Bacitracin D and L modified Cycloserine Natural product produced by Streptomyces garyphalus Inhibits L-alanine racemase and D-Ala-D-Ala ligase Blocks biosynthesis of D-Ala-D-Ala Mimics the structure of D-Ala

2. D-Cycloserine D

. 3. Bacitracin Polypeptide produced by Bacillus subtilis Cytoplasm Cell membrane NAM Carrier lipid L-Ala D-Glu L-Lys D-Ala D-Ala- D-Ala Amino acid NAG Gly . Transglycosidation Vancomycin Growing cell wall Crosslinking b-Lactams Cycloserine Bacitracin modified Polypeptide produced by Bacillus subtilis Binds to the carrier lipid Prevents the carrier lipid from transporting the NAM -pentapeptide building block across the cell membrane

. 4. Vancomycin and vancomycin analogues Cytoplasm Cell membrane NAM Carrier lipid L-Ala D-Glu L-Lys D-Ala D-Ala- D-Ala Amino acid NAG Gly . Transglycosidation Growing cell wall Crosslinking b-Lactams Bacitracin Cycloserine Vancomycin modified Narrow spectrum bactericidal glycopeptide Produced by Streptomyces orientalis Blocks transglycosidation

4. Vancomycin and vancomycin analogues Peptide chain Vancomycin Vancomycin receptor Important antibacterial agent Caps the building block used in the synthesis of the bacterial cell wall Contains a peptide chain which forms hydrogen bonds to the target Vancomycin acts as a receptor for the building block

4. Vancomycin and vancomycin analogues Biosynthesis of vancomycin Derived from a flexible hexapeptide Cyclisations result in a rigid structure Peptide backbone is held in a fixed conformation

4. Vancomycin and vancomycin analogues Mechanism of inhibition Vancomycin Building block Cell membrane Notes Vancomycin provides binding pocket for tail of biosynthetic building block Vancomycin binds to the tail of the building block’s peptide chain Caps the building block Disguises the building block from the transglycosidation enzyme

. . . . 4. Vancomycin and vancomycin analogues Dimerisation occurs Building block . Growing cell wall gkycnes Dimerisation occurs Dimer is highly stable Large vancomycin molecule acts as a steric shield

4. Vancomycin and vancomycin analogues L and D H-bonding interactions between the peptide backbone of vancomycin and the biosynthetic building block

4. Vancomycin and vancomycin analogues Binding interactions in dimer L and D

4. Vancomycin and vancomycin analogues Drug resistance Vancomycin-resistant Staphylococcus aureus (VRSA) (1996) Vancomycin-resistant enterococci (VRE) (1989) Resistance due to mutation in pentapeptide chain of cell wall building block Terminal D-alanine replaced by D-lactate Mutation Italics D La nd D Peptide link replaced by ester link Loss of NH (HBD) Weakens binding affinity of vancomycin with ‘tail’ Lactate acts as a leaving group in cell wall synthesis

4. Vancomycin and vancomycin analogues Teicoplanin Teicoplanin

4. Vancomycin and vancomycin analogues Teicoplanin Isolated from a soil micro-organism Does not dimerise Alkyl chain anchors the antibiotic to the outer surface of the cell membrane Less toxic than vancomycin Teicoplanin Cell membrane Building block Alkyl chain anchor Circles modified

4. Vancomycin and vancomycin analogues Eremomycin - naturally occurring glycopeptide

4. Vancomycin and vancomycin analogues LY 333 328 - analogue of eremomycin Biphenyl hydrophobic tail 1000 x more active than vancomycin

4. Vancomycin and vancomycin analogues Telavancin - analogue of eremomycin Hydrophobic tail Approved in 2009 for skin infections

4. Vancomycin and vancomycin analogues Simplification Simplified structures capable of binding D-Ala-D-Ala or D-Ala-D-Lac Lead compounds for further development D