Surface functionalized binary antibiotic nanoparticles of enhanced antimicrobial action

Abstract

Bacteria develop antimicrobial resistance (AMR) much faster than the discovery and the introduction of novel antibiotic drugs, which is an intricate and costly process. A potential solution is to find novel ways of reformulating already developed antibiotics. Here we propose a formulation of binary antibiotic nanoparticles fabricated from existing antibiotics which can strongly enhance their individual antimicrobial effects. These formulations consist of mixed nanocrystals of co-precipitated anionic antibiotic (e.g. sodium cefoperazone) and a cationic antibiotic (e.g. tetracycline hydrochloride) sterically stabilized with a surface-active polymer (Poloxamer 407) and further coated with a cationic surfactant. The cationic surface functionality is aimed to enhance the electrostatic adherence of the nanoparticles to the negatively charged bacterial cell walls leading to sustained simultaneous release of high local concentration of both antibiotics. These binary antibiotic nanoparticles are based on “safer-by-design” concept and can fully dissolve with time. We explored the antimicrobial effect of binary antibiotic particles of three different surface coatings:hexadecyl trimethylammonium bromide (HDTAB), octadecyl trimethylammonium bromide (ODTAB) and dioctadecyl dimethylammonium bromide (DODAB). The antimicrobial efficacy of the cationic surface-functionalized particles was evaluated on both Gram-negative and Gram-positive bacterial strains, Escherichia coli and Staphylococcus aureus. This approach resulted in an enhanced antimicrobial effect compared to the individual application of each of the free antibiotics at equivalent overall concentration. The produced binary antibiotic nano-delivery system showed low-to-moderate cytotoxicity on human cells. This may make them potentially applicable as injectable formulations as no nanocarrier is left post use. This innovative approach for reformulating pairs of existing antibiotics seems a promising way for breathing new life into existing antibiotics.