Infections by Carbapenem-resistant Enterobacteriaceae(CRE)producing New Delhi metallo-β-lactamases(NDMs)that hydrolyze carbapenems,are difficult to treat.Considering the fact of barren antibiotic development pipeline...Infections by Carbapenem-resistant Enterobacteriaceae(CRE)producing New Delhi metallo-β-lactamases(NDMs)that hydrolyze carbapenems,are difficult to treat.Considering the fact of barren antibiotic development pipeline nowadays,revitalizing carbapenems efficacy using antibiotic adjuvants represents a promising but as-yet-unrealized tactic in combating NDMs-producing CRE,because of their off-target distributions,weak permeability to the outer membrane(OM)barrier,and limited NDMs-inactivation ability.Here,a pathogen-anchoring nano electrosensitizer,is proposed for serving as electrodynamic therapy(EDT)-activatable antibiotic adjuvant to revitalize meropenem(MEM,a typical carbapenems),through layerby-layer assembly of platinum nanoclusters(PtNCs),MEM,and maltodextrin(MA).The MA corona of electro-driven nanosensitizer promotes the efficient anchoring of PtNCs and MEM onto the surface of pathogen.Triggered by a square-wave alternating current(AC),MEM is released,PtNCs-based EDT is activated,accompanied by the generation of electro-driven reactive oxygen(ROS)at the bacterial infectious microenvironment.Subsequently,the antibacterial efficacy of MEM is thereby restored against NDMs-producing CRE through the ROS-mediated cascading effect,including the OM destruction,MEM intracellular accumulation,and NDMs inactivation.By the cooperation of MA-mediated pathogen anchoring and EDT-induced dual action,the pathogen-anchoring nano electrosensitizer revitalizes MEM efficacy against clinically isolated NDMs-producing CRE in vitro,and in mice infection model,importantly,also slows down the development of higher-level resistance in NDMsproducing CRE.The pathogen-anchoring nano electrosensitizer can fully play the therapeutic potency of carbapenems,providing a promising approach to tackle NDMs producer-induced infections.展开更多
基金supported by the National Natural Science Foundation of China(No.82402470)Postdoctoral Science Foundation of China(No.2023M743207)+2 种基金Science and Technology Key Research Project of Henan Province(No.252102311187)Postdoctoral Fellowship Program of CPSF(No.GZC20232438)Major Science and Technology Projects in Henan Province(No.241110310600).
文摘Infections by Carbapenem-resistant Enterobacteriaceae(CRE)producing New Delhi metallo-β-lactamases(NDMs)that hydrolyze carbapenems,are difficult to treat.Considering the fact of barren antibiotic development pipeline nowadays,revitalizing carbapenems efficacy using antibiotic adjuvants represents a promising but as-yet-unrealized tactic in combating NDMs-producing CRE,because of their off-target distributions,weak permeability to the outer membrane(OM)barrier,and limited NDMs-inactivation ability.Here,a pathogen-anchoring nano electrosensitizer,is proposed for serving as electrodynamic therapy(EDT)-activatable antibiotic adjuvant to revitalize meropenem(MEM,a typical carbapenems),through layerby-layer assembly of platinum nanoclusters(PtNCs),MEM,and maltodextrin(MA).The MA corona of electro-driven nanosensitizer promotes the efficient anchoring of PtNCs and MEM onto the surface of pathogen.Triggered by a square-wave alternating current(AC),MEM is released,PtNCs-based EDT is activated,accompanied by the generation of electro-driven reactive oxygen(ROS)at the bacterial infectious microenvironment.Subsequently,the antibacterial efficacy of MEM is thereby restored against NDMs-producing CRE through the ROS-mediated cascading effect,including the OM destruction,MEM intracellular accumulation,and NDMs inactivation.By the cooperation of MA-mediated pathogen anchoring and EDT-induced dual action,the pathogen-anchoring nano electrosensitizer revitalizes MEM efficacy against clinically isolated NDMs-producing CRE in vitro,and in mice infection model,importantly,also slows down the development of higher-level resistance in NDMsproducing CRE.The pathogen-anchoring nano electrosensitizer can fully play the therapeutic potency of carbapenems,providing a promising approach to tackle NDMs producer-induced infections.
