Practice question

Gram-positive bacteria possess a uniquely thick, exposed mesh of peptidoglycan often 20 to 80 nm composed of many layers of glycan chains highly cross-linked, lacking an outer membrane that would otherwise act as permeability barrier. Vancomycin is a large hydrophilic glycopeptide of about 1449 Da with multiple aromatic rings and sugars, physicochemical properties that prevent efficient passage through porin channels and lipopolysaccharide outer membrane of Gram-negative bacteria but allow ready diffusion through porous peptidoglycan of Gram-positives. It binds non-covalently via five specific hydrogen bonds to the carbonyl and amide groups of the D-Ala-D-Ala terminus of Lipid II precursors, sequestering substrate from transglycosylase and transpeptidase enzymes. Without free substrate access, cell wall maturation halts and septal synthesis fails. The clinical consequence is potent bactericidal activity against Staphylococcus aureus including MRSA, Enterococcus faecalis and faecium, Streptococcus pneumoniae and Clostridioides difficile causing pseudomembranous colitis. Polymyxins target lipid A of lipopolysaccharide of Gram-negatives, aminoglycosides require oxygen-dependent uptake suited to Gram-negatives, while beta-lactams vary in spectrum, making vancomycin archetypal for Gram-positive coverage and reserve status.