Vancomycin, a
glycopeptide antibiotic, has long been a
drug of choice for life-threatening
Gram-positive bacterial infections.
Vancomycin confers its antibacterial activity by inhibiting bacterial cell wall biosynthesis. However, over the time,
vancomycin has also been rendered ineffective by
vancomycin-resistant bacteria (VRB). These bacteria developed resistance to it by alteration of cell wall precursor from
D-Ala-D-Ala to D-Ala-D-Lac (vancomycin-resistant Enterococci, VRE), which leads to manifold reduction in the binding constant and results in the loss of antibacterial activity. Herein, we report various
vancomycin-
sugar analogs, based on a simple design rationale, which exhibit increased binding affinity to VRB, thereby resensitizing VRB to
vancomycin. Optimized
vancomycin-
sugar conjugate exhibited 150-fold increase in affinity for N,N'-
diacetyl-Lys-D-Ala-D-Lac compared with
vancomycin. This improved binding affinity was also reflected in its antibacterial activity, wherein the MIC value was brought down from 750 to 36 μM against VRE (VanA phenotype). To further sensitize against VRE, we appended lipophilic alkyl chain to optimized
vancomycin-
sugar conjugate. This lipophilic-
vancomycin-
sugar conjugate was >1000-fold (MIC=0.7 μM) and 250-fold (MIC=1 μM) more effective against VanA and VanB strains of VRE, respectively, compared with
vancomycin. Therefore, this synthetically simple approach could lead to the development of new generation of
glycopeptide antibiotics, which can be clinically used to tackle VRB
infections.