Peptide–Polymer Conjugates: A Promising Therapeutic Solution for Drug-Resistant Bacteria

Abstract

By 2050, it is estimated that 10 million people will die of drug-resistant bacterial infection caused by antibiotic abuse. Antimicrobial peptide (AMP) is widely used to prevent such circumstances, for the positively charged AMPs can kill drug-resistant bacteria by destroying negatively charged bacterial cell membrane, and has excellent antibacterial efficiency and low drug resistance. However, due to the defects in low in vivo stability, easy degradation, and certain cytotoxicity, its practical clinical application is limited. The emergence of peptide–polymer conjugates (PPC) helps AMPs overcome these shortcomings. By combining with functional polymers, the positive charge of AMPs is partially shielded, and its stability and water solubility are improved, so as to prolong the in vivo circulation time of AMPs and reduce its cytotoxicity. At the same time, the self-assembly ability of PPC enables it to assemble into different nanostructures to undertake specific antibacterial tasks. At present, PPC is mainly used in wound dressing, bone tissue repair, antibacterial coating of medical devices, nerve repair, tumor treatment, and oral health maintenance. In this study, we summarize the structure, synthesis methods, and the clinical applications of PPC, so as to present the current challenges and discuss the future prospects of antibacterial therapeutic materials.

Antimicrobial Peptides Demonstrate Activity against Resistant Bacterial Pathogens

“…The use of the synthetic AMP E6, a 12-amino-acid peptide to coat catheters, prevented infectious disease in mouse models [ 9 ]. The AMP melimine has been covalently bound to contact lens surfaces using 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride, reducing the prevalence of lens-associated eye infection [ 44 ].…”

“…Research studies demonstrate that sublethal doses of AMPs melittin and pexiganan prime bacterial cells to increase both tolerance and persistence as demonstrated with E. coli [ 70 ]. Melittin has demonstrated anticancer activity, which is non-specific resulting in cytotoxicity and hemolytic activity [ 44 ]. Resistance to bacteriocins may occur when bacteria mimic the defense mechanisms of the producer strain, adapt the cell membrane or via enzymatic activity in a similar manner to antibiotic resistance [ 11 ] ( Figure 2 ).…”

“…Currently, AMPs are not broadly implemented in the treatment of infectious disease with the exception of colistin and gramicidin. Their biocompatibility and cytotoxicity in vivo greatly hinder their application parenterally, with nephrotoxicity and hepatoxicity being evident in some cases [ 44 , 54 ]. Indeed, the AMPs currently in use are considered last-resort antibiotic agents [ 6 , 50 ].…”

“…Encapsulation within delivery systems composed of synthetic polymers, polysaccharides, proteins, liposomes, or inorganic materials improves the immunogenicity, biocompatibility, and stability of peptide therapeutics [ 81 ]. Using biocompatible polymers as delivery systems for AMPs can improve in vivo stability, half-life, and reduce cytotoxicity [ 44 ]. Encapsulation in nanoparticle delivery systems may improve the targeting of intracellular pathogens such as clinically relevant M. tuberculosis , S. enterica, and L. monocytogenes [ 68 ].…”

“…At present, there is a sparsity of human in vivo studies detailing the biocompatibility profile of AMPs with studies currently limited to cytotoxicity and hemocompatibility. In accordance with the FDA and International Standards Organization (ISO), testing guidelines testing the sensitization, pyrogenicity, genotoxicity, reproductive toxicity, and more is required to achieve FDA approval [ 44 ].…”