Novel Vancomycin‐β‐Lactam Hybrids: Structure–Activity Relationships and Therapeutic Potential Against VISA and VRE

Antimicrobial resistance (AMR) poses a significant global public health challenge. Vancomycin and β-lactam antibiotics, critical for treating multidrug-resistant (MDR) bacterial infections, are hindered by resistant strains such as vancomycin-resistant Enterococci (VRE) and vancomycin-intermediate Staphylococcus aureus, as well as β-lactamase-mediated resistance. This article leverages the complementary mechanisms of these antibiotics, which target bacterial cell wall synthesis, to develop vancomycin-β-lactam hybrids as a novel strategy against AMR. Through chemical modification, β-lactam fragments were introduced at the carboxyl (C), resorcinol (R), and amine (N) termini of vancomycin, yielding multiple hybrid series. In vitro activity assays revealed that C-terminal modified vancomycin-penicillin hybrids exhibited superior efficacy, with compound 6a-6g reducing the minimum inhibitory concentration against strains such as VREs by 512-1024-fold compared to vancomycin, achieving activity comparable to oritavancin in certain strains. In vitro safety evaluations demonstrated low cytotoxicity of 6a against human kidney (HK2) and embryonic kidney (HEK293) cell lines. These findings establish 6a as a promising drug candidate, offering a novel therapeutic option for MDR infections.