The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-a...The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-associated infections exacerbate this problem due to their inherent antibiotic resistance and complex structure.Current antibiotic treatments struggle to penetrate biofilms and eradicate persister cells,leading to prolonged antibiotic use and increased resistance.Host defense peptides(HDPs)have shown promise,but their clinical application is limited by factors such as enzymatic degradation and difficulty in largescale preparation.Synthetic HDP mimics,such as poly(2-oxazoline),have emerged as effective alter-natives.Herein,we found that the poly(2-oxazoline),Gly-POX_(20),demonstrated rapid and potent activity against clinically isolated multidrug-resistant Gram-positive strains.Gly-POX_(20) showed greater stability under physiological conditions compared to natural peptides,including resistance to protease degradation.Importantly,Gly-POX_(20) inhibited biofilm formation and eradicated mature biofilm and demonstrated superior in vivo therapeutic efficacy to vancomycin in a MRSA biofilm-associated mouse keratitis model,suggesting its potential as a novel antimicrobial agent against drug-resistant Gram-positive bacteria,especially biofilm-associated infections.展开更多
Peptides exert important biological functions but their application is hindered by their susceptibility to proteolysis and poor stability in vivo.Thus,functional peptide mimics have drawn a great deal of attention to ...Peptides exert important biological functions but their application is hindered by their susceptibility to proteolysis and poor stability in vivo.Thus,functional peptide mimics have drawn a great deal of attention to address this challenge.Poly(2-oxazoline)s,a class of biocompatible and proteolysis-resistant polymer,can work as host defense peptide mimics without following the general membrane-targeting mechanism as shown in our previous work.This observation encouraged us to figure out if poly(2-oxazoline)s are special and break the general membrane-targeting mechanism of host defense peptides and their mimics.In this study,we aimed at the connection between structure and antibacterial mechanism of poly(2-oxazoline)s.A new γ-aminobutyric acid(GABA)-pendent poly(2-oxazoline)was synthesized and investigated to compare with glycine-pendent poly(2-oxazoline)in our previous study,with the former polymer has two extra CH2 groups in the sidechain to increase the hydrophobicity and amphiphilicity.Membrane depolarization assay suggested that incorporating two more CH2 groups into the sidechain of poly(2-oxazoline)resulted in a mechanism switch from DNA-targeting to membrane-targeting,which was supported by the slow time-kill kinetics and slightly distorted and sunken membrane morphology.Besides,GABA-pendent poly(2-oxazoline)showed potent activity against methicillin-resistant S.aureus and low hemolysis on human red blood cells.Moreover,repeated use of the antimicrobial poly(2-oxazoline)did not stimulate bacteria to obtain resistance,which was an obvious advantage of membrane-targeting antimicrobial agents.展开更多
It is an urgent need to tackle drug-resistance microbial infections that are associated with implantable biomedical devices.Host defense peptide-mimicking polymers have been actively explored in recent years to fight ...It is an urgent need to tackle drug-resistance microbial infections that are associated with implantable biomedical devices.Host defense peptide-mimicking polymers have been actively explored in recent years to fight against drug-resistant microbes.Our recent report on lithium hexamethyldisilazide-initiated superfast polymerization on amino acid N-carboxyanhydrides enables the quick synthesis of host defense peptide-mimicking peptide polymers.Here we reported a facile and cost-effective thermoplastic polyurethane(TPU)surface modification of peptide polymer(DLL:BLG=90:10)using plasma surface activation and substitution reaction between thiol and bromide groups.The peptide polymer-modified TPU surfaces exhibited board-spectrum antibacterial property as well as effective contact-killing ability in vitro.Furthermore,the peptide polymer-modified TPU surfaces showed excellent biocompatibility,displaying no hemolysis and cytotoxicity.In vivo study using methicillin-resistant Staphylococcus aureus(MRSA)for subcutaneous implantation infectious model showed that peptide polymer-modified TPU surfaces revealed obvious suppression of infection and great histocompatibility,compared to bare TPU surfaces.We further explored the antimicrobial mechanism of the peptide polymer-modified TPU surfaces,which revealed a surface contact-killing mechanism by disrupting the bacterial membrane.These results demonstrated great potential of the peptide-modified TPU surfaces for practical application to combat bacterial infections that are associated with implantable materials and devices.展开更多
Poly(β-peptoid)is a class of polypeptide mimics that possesses excellent biocompatibility and resistance to proteolysis.However,the synthesis of poly(β-peptoid)s with functionalities is a long-standing challenge tha...Poly(β-peptoid)is a class of polypeptide mimics that possesses excellent biocompatibility and resistance to proteolysis.However,the synthesis of poly(β-peptoid)s with functionalities is a long-standing challenge that greatly hinders the functional study and application of poly(β-peptoid)s.We report a controllable and easy synthesis of poly(β-peptoid)s bearing diverse functionalities via the ring-opening polymerization on N-substitutedβ-alanine N-thiocarboxyanhydrides(β-NNTAs).The polymerization can be carried out in openvesselsundermildconditions usingaminesas the initiators to provide poly(β-peptoid)s with targeted molecular weights,narrow dispersities,and diverse functionalities in the side chains and termini.Theβ-NNTAs polymerization is even compatible with initiators bearing unprotected hydroxyl groups.The amphiphilic/cationic poly(β-peptoid)s exhibit a broad spectrum and potent antibacterial activities against multidrug-resistant bacteria.In addition,the highly favored stability ofβ-NNTAmonomers for purification and storage highlights the advantages of thisβ-NNTA polymerization strategy for poly(β-peptoid)s synthesis,functional study,and application as a synthetic mimic of polypeptides.展开更多
基金financially supported by the National Key Research and Development Program of China(no.2022YFC2303100)National Natural Science Foundation of China(nos.T2325010,22305082,52203162,and 22075078)+1 种基金Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism(Shanghai Municipal Education Commission),the Fundamental Research Funds for the Central Universities(nos.JKVD1241029 and JKD01241701)Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry(Changchun Institute of Applied Chemistry,Chinese Academy of Sciences),the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology(Ministry of Education,no.R202201).
文摘The rising prevalence of drug-resistant Gram-positive pathogens,particularly methicillin-resistant Staphy-lococcus aureus(MRSA)and vancomycin-resistant Enterococci(VRE),poses a substantial clinical challenge.Biofilm-associated infections exacerbate this problem due to their inherent antibiotic resistance and complex structure.Current antibiotic treatments struggle to penetrate biofilms and eradicate persister cells,leading to prolonged antibiotic use and increased resistance.Host defense peptides(HDPs)have shown promise,but their clinical application is limited by factors such as enzymatic degradation and difficulty in largescale preparation.Synthetic HDP mimics,such as poly(2-oxazoline),have emerged as effective alter-natives.Herein,we found that the poly(2-oxazoline),Gly-POX_(20),demonstrated rapid and potent activity against clinically isolated multidrug-resistant Gram-positive strains.Gly-POX_(20) showed greater stability under physiological conditions compared to natural peptides,including resistance to protease degradation.Importantly,Gly-POX_(20) inhibited biofilm formation and eradicated mature biofilm and demonstrated superior in vivo therapeutic efficacy to vancomycin in a MRSA biofilm-associated mouse keratitis model,suggesting its potential as a novel antimicrobial agent against drug-resistant Gram-positive bacteria,especially biofilm-associated infections.
基金financially supported by the Natural Science Foundation of Shanghai(18ZR1410300)the National Natural Science Foundation of China(No.21861162010,21774031)+2 种基金the National Key Research and Development Program of China(No.2016YFC1100401)the Research Program of State Key Laboratory of Bioreactor Engineeringthe Fundamental Research Funds for the Central Universities(No.22221818014,50321041917001)。
文摘Peptides exert important biological functions but their application is hindered by their susceptibility to proteolysis and poor stability in vivo.Thus,functional peptide mimics have drawn a great deal of attention to address this challenge.Poly(2-oxazoline)s,a class of biocompatible and proteolysis-resistant polymer,can work as host defense peptide mimics without following the general membrane-targeting mechanism as shown in our previous work.This observation encouraged us to figure out if poly(2-oxazoline)s are special and break the general membrane-targeting mechanism of host defense peptides and their mimics.In this study,we aimed at the connection between structure and antibacterial mechanism of poly(2-oxazoline)s.A new γ-aminobutyric acid(GABA)-pendent poly(2-oxazoline)was synthesized and investigated to compare with glycine-pendent poly(2-oxazoline)in our previous study,with the former polymer has two extra CH2 groups in the sidechain to increase the hydrophobicity and amphiphilicity.Membrane depolarization assay suggested that incorporating two more CH2 groups into the sidechain of poly(2-oxazoline)resulted in a mechanism switch from DNA-targeting to membrane-targeting,which was supported by the slow time-kill kinetics and slightly distorted and sunken membrane morphology.Besides,GABA-pendent poly(2-oxazoline)showed potent activity against methicillin-resistant S.aureus and low hemolysis on human red blood cells.Moreover,repeated use of the antimicrobial poly(2-oxazoline)did not stimulate bacteria to obtain resistance,which was an obvious advantage of membrane-targeting antimicrobial agents.
基金This research was supported by the National Natural Science Foundation of China(No.22075078,21774031)the National Key Research and Development Program of China(2016YFC1100401)+4 种基金Program of Shanghai Academic/Technology Research Leader(20XD1421400)State Key Laboratory for Modification of Chemical Fibers and Polymer Materials,Donghua University,the Natural Science Foundation of Jiangsu Province(BK20180093)the Natural Science Foundation of Shanghai(18ZR1410300)Research program of State Key Laboratory of Bioreactor Engineering,the Fundamental Research Funds for the Central Universities(22221818014)The authors also thank Research Center of Analysis and Test of East China University of Science and Technology for the help on the characterization.
文摘It is an urgent need to tackle drug-resistance microbial infections that are associated with implantable biomedical devices.Host defense peptide-mimicking polymers have been actively explored in recent years to fight against drug-resistant microbes.Our recent report on lithium hexamethyldisilazide-initiated superfast polymerization on amino acid N-carboxyanhydrides enables the quick synthesis of host defense peptide-mimicking peptide polymers.Here we reported a facile and cost-effective thermoplastic polyurethane(TPU)surface modification of peptide polymer(DLL:BLG=90:10)using plasma surface activation and substitution reaction between thiol and bromide groups.The peptide polymer-modified TPU surfaces exhibited board-spectrum antibacterial property as well as effective contact-killing ability in vitro.Furthermore,the peptide polymer-modified TPU surfaces showed excellent biocompatibility,displaying no hemolysis and cytotoxicity.In vivo study using methicillin-resistant Staphylococcus aureus(MRSA)for subcutaneous implantation infectious model showed that peptide polymer-modified TPU surfaces revealed obvious suppression of infection and great histocompatibility,compared to bare TPU surfaces.We further explored the antimicrobial mechanism of the peptide polymer-modified TPU surfaces,which revealed a surface contact-killing mechanism by disrupting the bacterial membrane.These results demonstrated great potential of the peptide-modified TPU surfaces for practical application to combat bacterial infections that are associated with implantable materials and devices.
基金supported by the National Natural Science Foundation of China(nos.22075078 and 21861162010)the Free Exploring Basic Research Project at Shenzhen Research Institute of ECUST(no.2021Szvup042)+4 种基金the Program of Shanghai Academic/Technology Research Leader(no.20XD1421400)the National Natural Science Foundation of China for Innovative Research Groups(no.51621002)the China National Postdoctoral Program for Innovative Talents(no.BX2021102)the Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism(Shanghai Municipal Education Commission,grant 2021 Sci&Tech 03-28)the Research Program of the State Key Laboratory of Bioreactor Engineering,the Fundamental Research Funds for the Central Universities(no.JKD01211520).
文摘Poly(β-peptoid)is a class of polypeptide mimics that possesses excellent biocompatibility and resistance to proteolysis.However,the synthesis of poly(β-peptoid)s with functionalities is a long-standing challenge that greatly hinders the functional study and application of poly(β-peptoid)s.We report a controllable and easy synthesis of poly(β-peptoid)s bearing diverse functionalities via the ring-opening polymerization on N-substitutedβ-alanine N-thiocarboxyanhydrides(β-NNTAs).The polymerization can be carried out in openvesselsundermildconditions usingaminesas the initiators to provide poly(β-peptoid)s with targeted molecular weights,narrow dispersities,and diverse functionalities in the side chains and termini.Theβ-NNTAs polymerization is even compatible with initiators bearing unprotected hydroxyl groups.The amphiphilic/cationic poly(β-peptoid)s exhibit a broad spectrum and potent antibacterial activities against multidrug-resistant bacteria.In addition,the highly favored stability ofβ-NNTAmonomers for purification and storage highlights the advantages of thisβ-NNTA polymerization strategy for poly(β-peptoid)s synthesis,functional study,and application as a synthetic mimic of polypeptides.
