Polymyxin B Conjugates with Bio-Inspired Synthetic Polymers of Different Nature

Abstract

The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and the improvement of existing ones is a priority task. In this study, we proposed the synthesis of new polymeric conjugates of polymyxin B, which is a clinically approved but limited-use peptide antibiotic. In particular, three carboxylate-bearing polymers and one synthetic glycopolymer were selected for conjugation with polymyxin B (PMX B), namely, poly(,L-glutamic acid) (PGlu), copolymer of L-glutamic acid and L-phenylalanine (P(Glu-co-Phe)), copolymer of N-vinyl succinamic acid and N-vinylsuccinimide (P(VSAA-co-VSI)), and poly(2-deoxy-2-methacrylamido-D-glucose) (PMAG). Unlike PGlu and PMAG, P(Glu-co-Phe) and P(VSAA-co-VSI) are amphiphilic and form nanoparticles in aqueous media. A number of conjugates with different polymyxin B loading were synthesized and characterized. In addition, the complex conjugates of PGLu or PMAG with polymyxin B and deferoxamine (siderophore) were obtained. A release of PMX B from Schiff base and amide-linked polymer conjugates was studied in model buffer media with pH 7.4 and 5.8. In both cases, a more pronounced release was observed under slightly acidic conditions. The cytotoxicity of free polymers and PMX B as well as their conjugates was examined in human embryonic kidney cells (HEK 293T cell line). All conjugates demonstrated reduced cytotoxicity compared to the free antibiotic. Finally, the antimicrobial efficacy of the conjugates against Pseudomonas aeruginosa was determined and compared. The lowest values of minimum inhibitory concentrations (MIC) were observed for polymyxin B and polymyxin B/deferoxamine conjugated with PMAG. Among the polymers tested, PMAG appears to be the most promising carrier for delivery of PMX B in conjugated form due to the good preservation of the antimicrobial properties of PMX B and the ability of controlled drug release.

Bibliometric Review on New Possibilities of Antimycobacterial Agents: Exploring Siderophore Desferrioxamine’s Applications as an Antimicrobial Agent

“…Two authors independently screened articles based on their titles to identify duplicate articles and articles that met the exclusion criteria (e.g., case studies, protocols, letters, books, and reports unrelated to the topic of interest). Articles that could not be judged to meet the inclusion criteria based on their titles alone were retained for the next screening stage [ 17 ], which was completed on 30 June 2023. Thus, inclusion and exclusion criteria were used to limit the age range of the articles reviewed ( Table 4 ).…”

Bioinspired Polymers: Transformative Applications in Biomedicine and Regenerative Medicine

“…Polymeric conjugates of polymyxin B have exhibited reduced cytotoxicity and preserved antimicrobial properties against Pseudomonas aeruginosa [ 22 ]. These conjugates hold promise as carriers for controlled drug delivery, offering improved antibiotic efficacy and reduced side effects.…”

“…These polymers mimic the structure and function of natural peptides, offering a new approach to combat antibiotic-resistant bacteria. Additionally, bioinspired surface modifications, such as nanostructured surfaces and nanopatterned coatings, have been explored to inhibit bacterial attachment and biofilm formation, providing effective strategies for preventing infections [ 22 ].…”

Synthesis and Synergistic Antimicrobial Efficacy of Covalent Conjugates Composed of Epsilon-Poly-l-lysine and Beta-Lactam Antibiotics

“…Nevertheless, their relatively high cytotoxicity, difficulties in production and purification, low proteolytic stability, and susceptibility to salt in physiological environments hinder their clinical utility . Hence, various strategies have been utilized to adapt AMPs, such as entrapping AMPs into carriers synthesized with polymers, liposomes, or lipids, − modifying their sequences by repeating, substituting or functionalizing, − and altering of the molecule structure by branching, linearization or cyclization . Additionally, strategies like conjugating AMPs with other functional molecules, such as siderophores and polylactic acid nanoparticles, are also feasible. , However, the high investment, limited outcome, and lengthy cost-recovery period associated with developing entirely new antimicrobial agents have discouraged pharmaceutical companies .…”