Erythro-PmBs: A Selective Polymyxin B Delivery System using Antibody-Conjugated Hybrid Erythrocyte Liposomes

Due to the growing worldwide antibiotic resistance crisis, many currently available antibiotics have become ineffective as bacteria develop resistance mechanisms. Only a limited number of potent antibiotics can successfully suppress microbial growth; however, these are often considered a last resort due to their toxicity. We have developed a novel PmB delivery system by conjugating hybrid erythrocyte liposomes with antibacterial antibodies to combine high loading efficiency with targeted delivery [1,2]. The retention of PmB is enhanced through the incorporation of the negatively charged lipid, DMPS, into the red blood cell's cytoplasmic membrane through electrostatic interactions. Molecular dynamics (MD) simulations reveal an optimal fraction of DMPS in the hybrid erythrocyte membranes that allows for complete anchorage of PmB by inserting their acyl tail into the hydrophobic membrane core. Anti-Escherichia coli antibodies are attached to these hybrid erythrocyte liposomes using DSPE-PEG maleimide linkers. Our studies demonstrate that these erythro-PmBs have a loading efficiency of approximately 90% and effectively deliver PmB to E. coli, with minimum inhibitory concentration (MIC) values comparable to those of free PmB. However, the MIC values for Klebsiella aerogenes significantly exceeded the resistance breakpoint, indicating that the inclusion of anti-E. coli antibodies enables erythro-PmBs to selectively transport antibiotics to specific targets. MD simulations further suggest a fusion or lipid exchange mechanism between erythro-PmBs and the outer membrane of E. coli.<br/><br/>[1] Krivic, H., Himbert, S., Sun, R., Feigis, M. and Rheinstadter, M.C., 2022. Erythro-PmBs: A Selective Polymyxin B Delivery System Using Antibody-Conjugated Hybrid Erythrocyte Liposomes. ACS Infectious Diseases.<br/>[2] Krivic, H., Himbert, S. and Rheinstadter, M.C., 2022. Perspective on the Application of Erythrocyte Liposome-Based Drug Delivery for Infectious Diseases. Membranes, 12(12), p.1226.