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• W4385514055 abstract "Colistin is the last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections that are untreatable by other clinically available antibiotics. However, the recently merged plasmid-borne gene mobilized colistin resistance (mcr) leads to modification of the colistin target (i.e., bacterial membrane), greatly compromising the therapy outcome of colistin. To address this unmet clinical need, a nanocomplex (CMS-pEt_20 NP) of anionic prodrug colistin methanesulfonate (CMS) and guanidinium-functionalized cationic polymer pEt_20 is developed through facile self-assembly for co-delivering an antibiotic and antimicrobial polymer with membrane affinity to reverse colistin resistance. The CMS-pEt_20 NP formation enables reversal of colistin resistance and complete killing of clinically isolated mcr-positive colistin-resistant bacteria including MDR E. coli and K. pneumoniae, while monotreatment of polymer or antibiotic at equivalent doses exhibits no antibacterial activity. Mechanistic studies reveal that the CMS-pEt_20 NP enhanced the affinity of delivered CMS to the modified membrane of colistin-resistant bacteria, reviving the membrane lytic property of colistin. The increased membrane permeability caused by colistin in turn promotes an influx of pEt_20 to generate intracellular ROS stress, resulting in elimination of colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis infection model demonstrates the excellent therapeutic efficacy of CMS-pEt_20 NP with 100% survival of the infected mouse. In addition, the nanocomplex is proven not toxic both in vitro and in vivo. Taken together, the self-assembled antibiotic-polymer nanocomplex with two complementary antibacterial mechanisms successfully reverses the colistin resistance phenotype in bacteria, and it can be a potential strategy to treat untreatable colistin-resistant MDR bacterial infections." @default.
• W4385514055 created "2023-08-04" @default.
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• W4385514055 date "2023-08-03" @default.
• W4385514055 modified "2023-10-18" @default.
• W4385514055 title "Antibiotic–Polymer Self-Assembled Nanocomplex to Reverse Phenotypic Resistance of Bacteria toward Last-Resort Antibiotic Colistin" @default.
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• W4385514055 doi "https://doi.org/10.1021/acsnano.3c00981" @default.
• W4385514055 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37534992" @default.
• W4385514055 hasPublicationYear "2023" @default.
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