Modification of Vancomycin Structure to Combat against Emerging Vancomycin Resistance

Abstract The rise of multidrug‐resistant bacteria, such as Enterococcus faecium and Staphylococcus aureus , has compromised the efficacy of glycopeptide antibiotics like vancomycin. Consequently, novel strategies are urgently needed to combat vancomycin‐resistant strains. In this study, novel vancomycin derivatives with disulfide groups targeting the D‐alanyl‐D‐alanine for wild‐type, D‐alanyl‐D‐lactate, and D‐alanyl‐D‐serine regions for resistant strains were designed. Using ChemDraw Pro 12.0, the derivatives were created, and their binding affinities were assessed through molecular docking with AutoDock Vina. Molecular dynamics (MD) simulations were conducted with GROMACS 5.1.4, followed by MM/PBSA and quantum mechanical calculations. Pharmacokinetic properties were evaluated via ADMETlab 3.0. The derivatives showed enhanced binding energies across all target regions, irrespective of aromatic moieties or aliphatic groups. All three derivatives demonstrated higher logP values, improved gastrointestinal absorption, increased plasma protein binding percentages, better tissue distribution, and comparable half‐lives to vancomycin, along with favorable safety profiles. Among the vancomycin derivatives designed, derivative I emerged as a particularly promising candidate against vancomycin‐resistant strains, demonstrating superior binding energies and improved pharmacokinetic properties, thereby making it a strong candidate for further development.