Novel coumarin aminophosphonates as potential multitargeting antibacterial agents against Staphylococcus aureus

Unique coumarin aminophosphonates as new antibacterial agents were designed and synthesized to combat severely bacterial resistance. Bioactivity assessment identified that 3-hydroxylphenyl aminophosphonate 6f with low hemolytic activity not only exhibited excellent inhibition potency against Staphylococcus aureus at low concentration (0.5 mu g/mL) in vitro but also showed considerable antibacterial potency in vivo. Meanwhile, the active compound 6f was capable of eradicating the S. aureus biofilm, thus alleviating the development of S. aureus resistance. Furthermore, the drug combination of compound 6f with norfloxacin could enhance the antibacterial efficacy. Mechanistic explorations manifested that molecule 6f was able to destroy the integrity of cell membrane, which resulted in the leakage of protein and metabolism inhibition. The cellular redox ho-meostasis was interfered through inducing the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to the reduction of glutathione (GSH) activity and lipid peroxidation. Furthermore, compound 6f could intercalate into DNA base pair to hinder normal biological function. The above results provided powerful information for the further development of coumarin aminophosphonates as antibacterial agents.

Automated summary

This study designed and synthesized unique coumarin aminophosphonate compounds as new antibacterial agents, which exhibited excellent antibacterial activity and low toxicity. One of the compounds, 6f, showed remarkable inhibition against bacteria both in vitro and in vivo, and was capable of eradicating bacterial biofilms to prevent the development of bacterial resistance. Furthermore, the combination of compound 6f with norfloxacin enhanced the antibacterial efficacy. Mechanistic studies revealed that 6f could disrupt cell membrane integrity, interfere with redox homeostasis, and intercalate into DNA base pairs.