Vancomycin kills bacteria by binding to the D-Ala–D-Ala terminus of peptidoglycan precursors. Vancomycin-resistant Enterococcus (VRE) modifies this target to D-Ala–D-Lac. Which property of D-Lac reduces vancomycin binding?

• A D-Lac has an extra positive charge that electrostatically repels vancomycin
• B D-Lac causes conformational change in the peptidoglycan cross-bridge, preventing glycopeptide access
• C D-Lac substitutes an ester oxygen for an amide nitrogen, losing one hydrogen bond and creating steric clash ✓
• D D-Lac activates an efflux pump that removes vancomycin from the periplasm

Explanation

Vancomycin forms five hydrogen bonds with D-Ala–D-Ala. The terminal amide nitrogen of D-Ala donates a key hydrogen bond. When D-Ala is replaced by D-Lac (a depsipeptide), the nitrogen is replaced by an oxygen (ester linkage), which cannot donate that hydrogen bond; moreover, the lone pair on oxygen slightly repels the carbonyl of vancomycin. This single change reduces binding affinity approximately 1000-fold, conferring high-level resistance.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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