A traceless reversible polymeric colistin prodrug to combat multidrug-resistant (MDR) gram-negative bacteria

Area of Science:

• Pharmacology
• Drug Development
• Infectious Diseases

Background:

• Colistin is crucial for treating multidrug-resistant (MDR) Gram-negative bacterial infections.
• Colistin methanesulfonate (CMS) has slow and variable drug release, necessitating improved alternatives.
• There is an urgent need for more effective colistin prodrugs.

Purpose of the Study:

• To develop and evaluate a novel PEGylated colistin prodrug (col-aaPEG) with a cleavable linker.
• To assess the in vitro and in vivo efficacy and safety of col-aaPEG compared to CMS.
• To determine the potential of col-aaPEG as a superior alternative to CMS.

Main Methods:

• Synthesis of a PEGylated colistin prodrug (col-aaPEG) using a cleavable linker.
• In vitro antimicrobial activity assessment against MDR Pseudomonas aeruginosa and Acinetobacter baumannii using disk diffusion, broth dilution, and time-kill assays.
• In vivo efficacy evaluation in a mouse infection model and assessment of nephrotoxicity.

Main Results:

• The col-aaPEG prodrug releases active colistin in vitro within 24 hours.
• col-aaPEG demonstrated comparable or superior antimicrobial performance against MDR isolates compared to CMS.
• In vivo studies showed effective bacterial killing in a mouse model with no observed nephrotoxicity.

Conclusions:

• The PEGylated colistin prodrug (col-aaPEG) is a promising alternative to CMS.
• col-aaPEG offers improved efficacy and safety profiles for treating MDR Gram-negative bacterial infections.
• Further investigation of col-aaPEG is warranted for clinical application.