A new self-immolative colistin prodrug with dual targeting functionalities and reduced toxicity for the treatment of intracellular bacterial infections.

Abstract

Colistin is a potent antibiotic but its severe side effects including nephrotoxicity and neurotoxicity are the roadblock for their wide use in clinics. To solve this problem, we synthesized a new prodrug, mannose-maltose-colistin conjugate, termed MMCC that can reversibly mask the five amines of colistin that are primarily responsible for the toxicity. The deliberated design of disulfide-based self-immolative linker warranted the reversibly release of the pristine amines of colistin on demand without sacrificing antimicrobial efficacy. Once MMCC was delivered in cells, reducing agents cleaves the disulfide bond and release the pristine amines. The targeting ligands of maltose and mannose were grafted on colistin conjugate for targeting delivery of colistin to bacteria and macrophages, respectively. Taken together, MMCC as a new class of antimicrobial biomaterials, demonstrates its great potential for the treatment of intracellular bacterial infections.