Synergistic antimicrobial activity of a novel cationic micelle L/D2 and imipenem against multidrug-resistant Acinetobacter baumannii

Abstract

Background: The multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) has become one of the most important pathogens of nosocomial infection due to widespread use of broad spectrum antimicrobial drugs and immunosuppressor therapy. As polymyxins resistance emerges, developing novel effective antibacterial agents capable of overcoming multidrug resistance is urgently needed. Methods: In this study, biodegradable triblock copolymers of polyethylene glycol (PEG), guanidinium-functionalized polycarbonate and polylactide, PEG-PGC₂₀-PLLA₂₀ (L2) and PEG-PGC₂₀-PDLA₂₀ (D2), were utilized as antibacterial agents. Results: The copolymers self-assemble into micellar nanoparticles (L/D2), and exhibit broad-spectrum antibacterial activity against 20 clinically isolated multidrug-resistant A. baumannii strains. L/D2 had more rapid killing kinetics than conventional antibiotics imipenem and ceftazidime, and exhibited potent anti-biofilm activity. Repeated use of L/D2 did not induce drug resistance. From scanning electron microscopy and nucleic acid release analyses, L/D2 showed membrane-lytic mechanism. We also demonstrated that L/D2 was synergistically active with imipenem against MDR A. baumannii strains. Additionally, strong synergistic antibacterial activity was also observed for the combined use of L/D2 and imipenem in a MDR A. baumannii abdominal infection mouse model. Conclusions: Therefore, the combination of L/D2 and imipenem might be an alternative option for the prevention of nosocomial infection caused by A. baumannii.

Keywords: Acinetobacter baumannii; Antimicrobial polymer; Micelle; Multidrug resistance; Synergistic antimicro-bial activity.