摘要
Biofilm-associated bacterial infection brings serious threats to global public health owing to serious antibiotic resistance.It is urgently needed to develop innovative strategies to combat biofilm-associated bacterial infections.Polymyxins stand out as the last line of defense against Gram-negative bacteria.However,serious nephrotoxicity of polymyxins severely limits their clinical utility.Herein,a hypoxia-responsive liposome is designed as the nanocarrier of polymyxin B(PMB)to combat biofilms developed by Gram-negative bacteria.A metronidazole modified lipid(hypoxia-responsive lipid(HRLipid))is synthesized to fabricate hypoxia-responsive liposomes(HRLip).PMB loaded hypoxia-responsive liposomes(HRL-PMB)is then prepared to mitigate the nephrotoxicity of PMB while preserving its excellent bactericidal activity.HRL-PMB shows very low hemolysis and cytotoxicity due to liposomal encapsulation of PMB.PMB can be readily released from HRL-PMB in response to hypoxic biofilm microenvironment,exerting its bactericidal activity to realize biofilm eradication.The excellent in vivo antibiofilm ability of HRL-PMB is confirmed by a Pseudomonas aeruginosa infected zebrafish model and a P.aeruginosa pneumonia infection model.Meanwhile,HRL-PMB can greatly reduce the nephrotoxicity of PMB after intravenous injection.The hypoxia-sensitive liposomes held great promise to improve the biosafety of highly toxic antibiotics while preserving their intrinsic bactericidal ability,which may provide an innovative strategy for combating biofilm-associated infections.
基金
supported by the National Natural Science Foundation of China(Nos.52293381 and 52273154)
the Key Project of Natural Science Foundation of Zhejiang Province(No.LZ23B040002).
