Co-delivery of ampicillin and β-lactamase inhibitor by selenium nanocomposite to achieve synergistic anti-infective efficiency through overcoming multidrug resistance

Bacterial infective diseases due to antibiotic resistance remain a great challenge in clinic. Design of novel antibacterial drugs with high efficiency and low side effects to overcome antibiotic resistance is urgently needed. Herein, M-Cs (mannose- modified chitosan) modified selenium (Se) nanoparticles to co-deliver ampicillin (Ap) and β-lactamase inhibitor were synthesized and characterized (SAMCP NPs). Mannose modification endowed SAMCP NPs with enhanced recognition of bacteria by FimH lectin. Co-delivery of ampicillin and β-lactamase inhibitor (3-carboxyphenylboronic acid, Pba) by selenium nanocomposite (30 μg/mL) effectively inhibited β-lactamase activity, which synergistically enhanced ampicillin-induced antibacterial activity against ampicillin-resistant Escherichia coli (E. coli (R)) in vitro by suppression of AcrAB-TolC efflux pump system through eliminating ROS. SAMCP NPs (5 mg/kg) in vivo also showed synergistic anti-infective efficiency by inhibiting E. coli (R) infection-induced inflammatory response, cell apoptosis and regulating multiple signal pathways, and eventually promoted wound healing of mice. Importantly, SAMCP NPs displayed low toxicity and low side effects in vivo. Our findings validated our rational design that co-delivery of ampicillin and β-lactamase inhibitor by selenium nanocomposite to overcome multidrug resistance could be a highly efficient way to achieve antibacterial synergy.