Development of Xanthoangelol-Derived Compounds with Membrane-Disrupting Effects against Gram-Positive Bacteria
Siyu Yang,
Fangquan Liu,
Yue Leng,
Meiyue Zhang,
Lei Zhang,
Xuekun Wang,
Yinhu Wang
Affiliations
Siyu Yang
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
Fangquan Liu
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
Yue Leng
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
Meiyue Zhang
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
Lei Zhang
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
Xuekun Wang
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
Yinhu Wang
State Key Laboratory for Macromolecule Drugs and Large-Scale Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, Liaocheng 252059, China
Infections caused by multidrug-resistant pathogens have emerged as a serious threat to public health. To develop new antibacterial agents to combat such drug-resistant bacteria, a class of novel amphiphilic xanthoangelol-derived compounds were designed and synthesized by mimicking the structure and function of antimicrobial peptides (AMPs). Among them, compound 9h displayed excellent antimicrobial activity against the Gram-positive strains tested (MICs = 0.5–2 μg/mL), comparable to vancomycin, and with low hemolytic toxicity and good membrane selectivity. Additionally, compound 9h demonstrated rapid bactericidal effects, low resistance frequency, low cytotoxicity, and good plasma stability. Mechanistic studies further revealed that compound 9h had good membrane-targeting ability and was able to destroy the integrity of bacterial cell membranes, causing an increase in intracellular ROS and the leakage of DNA and proteins, thus accelerating bacterial death. These results make 9h a promising antimicrobial candidate to combat bacterial infection.
