Traceless antibiotic-crosslinked micelles for rapid clearance of intracellular bacteria
Effective delivery of antimicrobial agents to intracellular pathogens represents a major bottleneck for a wide variety of infectious diseases. To address this, we developed SIR-micelles(+), as a new delivery vehicle comprising antibiotic-loaded micelles with rapid self-immolation within cells for targeted delivery to macrophages, where most intracellular bacterial reside. After phagocytosis, SIR-micelles(+) rapidly release the pristine antibiotic after the cleavage of the disulfide bonds by intracellular reducing agents such as glutathione (GSH). Colistin , a hydrophilic and potent “last-resort” antibiotic used for the treatment of drug-resistant bacterial infection, was encapsulated in SIR-micelles with 40% yield and good short-term storage stability. Hydrophobic moieties and mannose ligands in SIR-micelles(+) enhanced the delivery of colistin into macrophages. The traceless and thiol-responsive release of colistin effectively eliminated intracellular Escherichia coli within twenty minutes. In a murine pneumonia model, SIR-micelles(+) significantly reduced bacterial lung burden of multidrug-resistant Klebsiella pneumoniae . Furthermore, SIR-micelles(+) improved the survival rate and reduced the bacterial burden of organs infected by intracellular bacteria transferred from donor mice. Using this formulation approach, the nephrotoxicity and neurotoxicity induced by antibiotic were reduced by about 5– 15 fold. Thus, SIR-micelles(+) represent a new class of material that can be used for targeting treatment of intracellular and drug-resistant pathogens.
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