11 Vancomycin Duncan Flashcards
What is some general information of Vancomycin?
A complex antibiotic isolated from Steptomyces orientalis. Formed of unusual amino acids and sugars hence the name: Glycopeptide. Primarily active against Gram (+) bacteria; most Gram (-) species and mycobacteria are resistant
What is the structure of Vancomycin like?
Tricyclic structure. Linear heptapeptide, fused in 3 rings. Two sugars: terminal vancosamine. Synthesized by NRPS modular genes/proteins (NRPS)
What are the characteristics like of the sugars that are in Vancomycin?
Deglycosylated form is active (termed “aglycone”). Hence, sugars don’t contribute to activity: but the true story is much more complex. Resistance to vancomycin occurs. Modification to vancosamine can overcome it
What is the general class of vancomycin antibiotics referred to as?
Glycopeptide Antibiotics
What does Vancomycin do?
Inhibits cell wall biosynthesis. Inhibition prevents addition of disaccharide building block to cell wall. Inhibits the transpeptidation reaction (stage III)
What are the metabolic processes affected?
Blocks cell wall biosynthesis. Inhibition is non-enzymatic. Occurs by steric interference mechanism
What is the mechanism of inhibition from vancomycin?
The peptide protion of the molecule binds to the D-ala-D-ala tail of the pentapeptide (lock-and-key)
What is the MOA of Vancomycin?
Creates steric interference for enzymes that must recognize this part of the cell wall precursor (“gum on the key”): transpeptidase, transglycosylase. Primary inhibition is at the final amino acid cross-linking step (transpeptidase; like B-lactams)
For Vancomycin how does it affect the role of sugars?
Causes immature peptidoglycan to form, but can’t be made into the mature peptidoglycan
What does modifying the sugar on vancomycin do?
Mod sugar R groups counteracts resistance
What is the role of the sugars on Vancomycin?
The sugars alone can exhibit antibiotic activity (when modified with the membrane-targeting chlorobiphenyl). The sugars block the incorporation of lipid II into the growing peptidoglycan (lipid II accumulates). Hence, they block the activity of transglycosylase. Thus, glycopeptides can be a bipartite, bifunctional antibiotic
What are the two main types of highly resistant strains to vancomycin?
VanA and VanB. Both are plasmid mediated. Both contain virtually identical genes
What is the biosynthetic pathway of vancomycin resistant species?
Have an altered cell wall biosynthetic pathway. The final cell wall is unaltered. However, the intermediate N-acetyl-muramic acid penta “peptide” has a D-ala-D-lac tail, instead of D-ala-D-ala. This in essence alters the shape of the “lock” that vancomycin recognizes. VISA, VRE (mechanism of resistance may differ). The genetic basis for this property (for VRE): plasmid-encoded, requires two different functionalities, synthetic, and degradative
What are the genes in the plasmid like for the vancomycen resistant enterococci?
Has new genes: VanH and VanA that make a new tail. VanX cleaves D-ala-D-ala whenever it sees it do stop it from competing with the new tail synthesis
What is VanA vs. VanB resistance?
VanA plasmid provides resistance to vancomycin AND teicoplanin. VanB plasmid provides resistance to vancomycin but NOT teicoplanin. VanB remains sensitive to teicoplanin because the Van HAX cassette is NOT activated (no cell wall precursor change occurs). Teicoplanin does NOT activate the RS sensor system in VanB-type plasmid (the S sensor is a histadine kinase, the R regulator is a transcription factor)