Synthesis And Antibacterial Properties Of Mimetic Antimicrobial Peptide Amino Acid Derivative Antibacterial Agents And Hydrogels

Antimicrobial peptides（AMPs）have been used as a new type of membrane-active antibacterial agent,which is of great significance to solve the problem of microbial resistance caused by antibiotic abuse.However,AMPs have disadvantages such as poor proteolytic stability,difficulty in preparation,and high price,which hinder their clinical application.Therefore,inspired by the antibacterial mechanism of AMPs,researchers have developed imitation AMPs compounds with AMPs structures,which have many advantages such as high antibacterial activity,low tendency to induce drug resistance,good biocompatibility and low cost.It has become a new research hotspot in the field of biomedicine.However,the current research on amino acid derived peptide mimics was still in its infancy,with limited types,low drug properties,relatively simple function and high cost.In particular,the influence of molecular structure of amino acid derived peptide mimics on their antibacterial activities is not clear,which seriously limits the design and development of novel high performance amino acid derived peptide mimics.In response to the above problems,based on the principle of cationic/hydrophobic balance,a series of novel amino acid-derived antibacterial peptide simulators were designed and synthesized from the perspective of changing molecular structure,and the influence of molecular structure of cationic peptide simulators on antibacterial activity was explored.Based on the designed antimicrobial peptide mimics,two star-shaped polyetheramide cross-linked antibacterial hydrogel materials were constructed,which provided technical reserves and data support for the antibacterial application of antimicrobial peptide mimics in the field of materials.The following research results have been achieved:Considering the structure design,a series of novel cationic AMPs mimics containing alkyl chains of different lengths（butyl to hexadecyl）and amino acid residues were designed and synthesized.The effect of long-chain hydrophobicity on antibacterial activity was ascertained and the structure-activity relationship was summarized.Hydrophobicity has a parabolic relationship with antibacterial activity,and the chain length corresponding to the best activity is dodecyl compounds.A-V-C₁₂ derived from dodecyl valine can not only kill common bacteria,but also has excellent antibacterial activity against methicillin-resistant Staphylococcus（MRSA）,with a minimum inhibitory concentration（MIC）of 8.3μg/m L.And it has good blood compatibility and low cytotoxicity.Simultaneously,the drug-resistant tendency test also confirmed the low drug-resistant tendency of the compound.Based on the dominant skeleton of rigid conjugation of benzene ring,a series of new cationic amino acid phenylamides were designed and synthesized by modifying natural amino acids.The antibacterial activity was evaluated and the influence of the substituents in the benzene ring skeleton on the antibacterial activity was given.The substituents of the ethynyl conjugated structure could significantly improve the antibacterial activity.The amino acid phenylamide P-V-18（containing L-valine residue and p-acetylene benzamide substituent）had an MIC value of 5μg/m L against drug-resistant bacteria MRSA.P-V-18 has the advantages of fast bactericidal speed（when the concentration is 4 times the MIC,more than 99.6%of the tested bacteria were killed within 1 hour）,low hemolytic activity(HC₅₀=891μg/m L),and low cytotoxicity.Antibacterial mechanism has shown that P-V-18 exerts antibacterial activity by destroying the integrity of the cell membrane and causing the leakage of macromolecules such as DNA.Moreover,studies on the tendency of drug resistance had confirmed that P-V-18 had low tendency to induce bacterial drug resistance,so it can be used as a new type of antibacterial agent to combat bacterial drug resistance.Based on the three-dimensional topology design,a series of star-shaped amino acid polyetheramides were designed and synthesized,and the star-shaped polyetheramine T403was used for condensation reaction with amino acids.The antibacterial activity of star amino acid polyetheramide against infection bacteria and drug-resistant bacteria was evaluated,and the relationship between the type and configuration of amino acid and antibacterial activity was summarized.The results showed that tryptophan polyetheramide（T-W-29）had the strongest antibacterial activity,and its MIC value against hospital-infected bacteria was 0.5～8μg/m L.In mammalian body fluids,the MIC value of T-W-29 against E.coli was 2.8μg/m L,showing excellent body fluid stability.T-W-29 also had the ability to quickly clear mature biofilms,and it cleared 95.5%of E.coli biofilms at a concentration of 256μg/m L.The results of flow cytometry,ion detection and microstructure characterization showed that amino acid polyetheramide could cause bacterial cell membrane lysis and DNA leakage.In addition,amino acid polyetheramides also exhibited the advantages of low hemolytic activity and low in vitro/in vivo toxicity,and have the potential to become new antibacterial agents.On this basis,the antibacterial application research of star amino acid polyetheramide in hydrogel materials was carried out.First,lysine-polyetheramide/polyacrylic acid antibacterial hydrogel with rapid self-healing and good mechanical properties was prepared by introducing lysine-polyetheramide into the polymeric network of acrylic acid through ionic interaction.The hydrogel could kill almost all adherent bacteria within 8 h,and its antibacterial properties could last for more than 7 days,showing long-term stable antibacterial activity.In addition,the hydrogel had good mechanical properties and self-healing ability,and its elongation at break reached 758%.Moreover,the elongation at break of the hydrogel recovered to 98.7%of the original hydrogel after 30 min of self-healing.Subsequently,based on the tyrosine polyetheramide benzene ring structure and its inherent antibacterial advantages,an electronic skin material with both antibacterial ability and human health detection function was prepared.The material was obtained by blending tyrosine polyetheramide with polyvinyl alcohol and polydopamine with conductivity and self-adhesiveness.The material had good electrical conductivity and could be used as a sensor to successfully detect the macroscopic（walking,running,etc.）and microscopic（swallowing,pulse beating,etc.）movements of the human body.And it had realized fast self-healing within 1s without external force interference.In addition,the inhibition zone diameters of the material against E.coli and S.aureus reached35.2 and 39.0 mm,and did not decrease within 7 days.It also exhibited low hemolytic activity.Therefore,the electronic skin material can not only avoid bacterial contamination during the sensing and detection process,but also serve as a real-time biosensing detection material for the wound skin healing process.