Glycopeptide/Membrane-Active MedChem

Question 1

Vanco

Answer 1

• Glycoslylated heptapeptide
• Mainly used IV in hospital
• Sometimes PO to treat GI infections like C. Diff
• Acts on D-ala-D-ala segment of cell wall in different manner than B-lactams
• High affinity for D-ala-D-ala via 5 hydrogen bonds

Question 2

Vanco MoA

Answer 2

• Binds to D-ala-D-ala residues on the peptidoglycan monomers
• No longer a suitable substrate for PBP
• No cross links are created and the weak cell wall is prone to intense osmotic pressure
• Leads to cell rupturing

Question 3

Thickened Cell Walls

Answer 3

• One mechanism of resistance against vanco
• Cell walls measuring 31.3 nm compared to VSSA strains of 23.4 nm
• Only intermediate resistance is produced

Question 4

Modification of PG Terminal

Answer 4

• Mechanism of resistance against Vanco
• Bacteria with adjusted genes like Van S, R, H, and X
• Modify the cell-wall biosynthetic pathway resulting in D-ala–D-lactate termini instead of D-ala-D-ala
• Only 4 hydrogen bonds can be formed with vanco and high levels of vanco resistance are seen
• > 200x lower binding constant going from 5 to 4 hydrogen bonds

Question 5

Lipoglycopeptides

Answer 5

• Telavancin (Vibativ) - semisynthetic, better PKPD than Vanco
• Dalbavancin (Dalvance) - 1 weekly IV dosing, similar drug
• Oritavancin (orbactive) - single IV dosing, thought to also bind to pentaglycine and Cl-biphenyl membrane and disrupt the plasma membrane

Question 6

Cubicin

Answer 6

• Daptomycin
• Lipopeptide (large molecule)
• Inserts into Gram “+” cell membrane, but much more complicated with multiple downstream effects
• Hydrophobic tail somehow involved in inserting into lung surfactant, lowering the free levels in lungs
• DO NOT USE IN TREATING PNEUMONIA

Question 7

Colistin

Answer 7

• Cyclic peptide
• Used against Gram “-“ bacteria
• Binds to LPS and disrupts membrane
• Hydrophobic tail, so can be used IV, topically, and inhaled
• Last line in many cases