Design And Evaluation Of Drug-Based On Two Polysaccharide Carriers Antibacterial

The chronic infections caused by pathogenic bacteria through bacterial biofilms and intracellular bacteria are always difficult to be cured because of the certain resistance to both antimicrobial agents and host defenses,which always be affceted by bacterial biofilms and intracellular bacteria.Especially in the current environment of lack of new antibiotics or highly effective antibacterial agents or effective strategies,the use of aminoglycoside antibiotics or natural antibacterial agents is facing major challenges in sterilization.In the existing treatment strategies,it is often used to increase the dose of antibiotics therapy for a long time.However,these methods not only greatly increase the toxic and side effects of antibiotics,but also lead to the emergence of drug-resistant bacteria.Over time,this will not be conducive to human development.Therefore,by improving the existing methods of administration of antibiotics or antibacterial agents,increasing their targeting and efficacy,and reducing their doses,they can provide a better solution for the treatment of chronic infections caused by bacterial biofilms and intracellular bacteria.In this study,two methods of drug delivery based on polysaccharides were designed.They were loaded with the aminoglycoside antibiotic amikacin and the natural antibacterial agent thymol,and evaluated their effects on the removal and destruction of intracellular bacteria and bacterial biofilms.1.Synthesis of hyaluronan-amikacin conjugate and its bactericidal activity against intracellular bacteria in vitro and in vivo.The functional carboxyl group of hyaluronic acid(12W)and propargylamine were derivatized with alkynyl hyaluronic acid under the catalysis of amidation condensation catalyst HATU.Protection of Amikacin Amino by Boc and catalysis of its 6'' hydroxide with Sodium Azide catalyzed by Triisopropylbenzenesulfonyl Chloride to form Amikacin with Azide,both occur under cuprous ion conditions targeted click response.It is a successful method to synthesis of hyaluronan-amikacin conjugate.Models of intracellular bacteria infected by Gram-positive bacteria(Listeria,Staphylococcus aureus)and Gram-negative bacteria(Pseudomonas aeruginosa)were established.The ability of the new conjugate to scavenge intracellular bacteria was determined and its clearance effect was found to be significantly higher than that of amikacin alone.Establishment of an animal model of Listeria acute infection of mice in the abdominal cavity.The ability of the new conjugate to clear bacteria in vivo was determined and it was found that the effect of the new conjugate on scavenging mouse kidney and spleen organs was higher than that of amikacin alone.The hyaluronic acid-amikacin conjugate can be carried by the macrophage surface CD44 vector into the infected cell,allowing the antibiotic to contact the intracellular bacteria.2.The photosensitizer toluidine blue is grafted on the amino group of chitosan(3KDa)through an amide reaction,and this hydrophilic molecular chain is linked to a carboxyl-containing hydrophobic polygarlic(carboxyl-terminated polysulfide,7KDa).Amphiphilic polymers are formed.The lipid-soluble thymol is encapsulated in an aqueous solution and self-assembled into a drug-loaded micelle.Toluidine blue generates active oxygen under light conditions.Polyallicin can be changed from hydrophobic to hydrophilic in a small amount of active oxygen environment to achieve micelle turnover and drug release.Remove bacteria from biofilms.At the same time,chitosan and excess active oxygen contribute to the destruction of bacterial biofilms,and polyallicin is also a good bacteriostatic agent.By establishing a biofilm model of Staphylococcus aureus and Listeria,it was determined that the activity of drug-loaded micelles to destroy biofilms was higher than that of drug alone.In summary,two kinds of polysaccharide-based drug design are feasible,which can improve the antibacterial activity of the drug,at the same time,it can reduce the amount of drug and antibacterial time,and reduce the toxic and side effects of drugs.