Biosynthetic ε-poly-L-lysine for the treatment of extensively- and pan-drug-resistant Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa (PA) represents a major cause of antimicrobial resistance-related morbidity and mortality. The recent emergence of highly fatal infections, caused by carbapenem-resistant PA, has called for novel antimicrobial therapies and strategies. In this study, we highlight the therapeutic potential of ε-poly-L-lysine (εPL), an antimicrobial polymer for treating extensively-and pan-drug-resistant-PA. εPL displayed potent antimicrobial activity against all eight drug-resistant PA, including carbapenem- and polymyxin-resistant PA. It exhibited a low risk of AMR evolution, with no evidence of cross-resistance with polymyxin B (a last-line treatment for drug-resistant Gram-negative bacteria). We further demonstrated promising in vivo efficacy and safety of εPL against PA in a pre-clinical PA keratitis model, with comparable effects to topical levofloxacin (a gold standard treatment of infectious keratitis) in terms of clinical scoring, corneal health/thickness, and bacterial bioburden. In view of its broad-spectrum antimicrobial activity, low risk of AMR evolution and cross-resistance with existing last-line antibiotics, and general acceptance of safety when orally administered, εPL serves as a promising novel antimicrobial agent for further clinical development and translation to tackle antimicrobial resistance.