Hydantoin derivative dimers as broad-spectrum antimicrobial agents against ESKAPE pathogens with enhanced killing rate and stability

Abstract

A new series of hydantoin derivative dimers as potential broad-spectrum antibiotic agents is designed and synthesized to combat ESKAPE pathogens. As membrane-active antimicrobial agents, in addition to cationic charged and hydrophobic groups that mimic AMPs (antimicrobial peptides), hydantoin backbones and aromatic linkers increased the rigidity and lipophilicity of the designed compounds, thus improving the stability and bactericidal killing rate. After whole cell phenotypic screening against eight bacterial strains, including MRSA (methicillin-resistant S. aureus), compound 18 was chosen as the lead compound with overall excellent broad-spectrum antibacterial activity (GM = 7.32 μg mL⁻¹) and good selectivity. Kill-kinetic studies of compound 18 showed that the bacterial growth of both Gram-positive and Gram-negative was completely inhibited within one hour, which demonstrated excellent sterilization efficiency of 18. Furthermore, drug resistance and mechanism studies showed that compound 18 exhibited a steady antibacterial performance during 25 passages and could disrupt bacterial cell membrane integrity and cause cell death. Along with the facile synthesis procedures in solution, this series of hydantoin derivative dimer compounds could be an appealing next generation of antibiotic agents to combat emergent drug resistance.