Single Amine\nor Guanidine Modification on Norvancomycin\nand Vancomycin to Overcome Multidrug-Resistance through Augmented\nLipid II Binding and Increased Membrane Activity

Vancomycin\nand norvancomycin have diminished antibacterial\nefficacy\ndue to acquired or intrinsic resistance from mutations in the terminal\ndipeptide of lipid II in Gram-positive bacteria or failure to penetrate\ninto the periplasm in Gram-negative bacteria. Herein, we rationally\ndesigned and synthesized a series of vancomycin analogues bearing\nsingle amine or guanidine functionality, altering various linkers\nand modification sites, to combat the resistance. Extensive antibacterial\nscreening was performed to delineate a comprehensive SAR. Many derivatives\nrevitalized the activity in vitro, exhibiting a 4–128-fold\nor 2–16-fold enhancement against the acquired or intrinsic\nresistance with lower toxicity. Significantly, the optimal compound <b>4g</b> demonstrated greater pharmacokinetic and pharmacodynamic\nprofiles. Further studies uncovered additional independent and synergistic\nmechanisms for <b>4g</b>, including the enhanced membrane activity\nand augmented inhibition of peptidoglycan biosynthesis via increased\nlipid II binding, highlighting its potential as a future lead candidate\nto replenish the glycopeptide antibiotic arsenal.