A novel combination therapy for multidrug resistant pathogens using chitosan nanoparticles loaded with β-lactam antibiotics and β-lactamase inhibitors

• Published in: International journal of biological macromolecules 2022-01, Vol.195, p.506-514
• Main Authors: Fan, Peixin, Ma, Zhengxin, Partow, Arianna J., Kim, Miju, Shoemaker, Grace M., Tan, Ruwen, Tong, Zhaohui, Nelson, Corwin D., Jang, Yeongseon, Jeong, Kwangcheol C.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; beta-Lactamase Inhibitors - administration & dosage; beta-Lactamase Inhibitors - pharmacology; Cephalosporins - pharmacology; Chemical Phenomena; Chitosan - chemistry; Chitosan nanoparticles; Drug Carriers - chemistry; Drug Combinations; Emulsion; Emulsions; Humans; Microbial Sensitivity Tests; Microbial Viability - drug effects; Nanoparticles - chemistry; β-lactamase inhibitor
• ISSN: 0141-8130; 1879-0003
• DOI: 10.1016/j.ijbiomac.2021.12.035

Antimicrobial resistance is one of the greatest global threats. Particularly, multidrug resistant extended-spectrum β-lactamase (ESBL)-producing pathogens confer resistance to many commonly used medically important antibiotics, especially beta-lactam antibiotics. Here, we developed an innovative combination approach to therapy for multidrug resistant pathogens by encapsulating cephalosporin antibiotics and β-lactamase inhibitors with chitosan nanoparticles (CNAIs). The four combinations of CNAIs including two cephalosporin antibiotics (cefotaxime and ceftiofur) with two β-lactamase inhibitors (tazobactam and clavulanate) were engineered as water-oil-water emulsions. Four combinations of CNAIs showed efficient antimicrobial activity against multidrug resistant ESBL-producing Enterobacteriaceae. The CNAIs showed enhanced antimicrobial activity compared to naïve chitosan nanoparticles and to the combination of cephalosporin antibiotics and β-lactamase inhibitors. Furthermore, CNAIs attached on the bacterial surface changed the permeability to the outer membrane, resulting in cell damage that leads to cell death. Taken together, CNAIs have provided promising potential for treatment of diseases caused by critically important ESBL-producing multidrug resistant pathogens. [Display omitted] •Chitosan nanoparticles loaded with antibiotic and enzyme inhibitor were engineered.•The encapsulated nanoparticles effectively inhibited multidrug resistance pathogens.•The nanoparticles enhanced the antibacterial activity of chitosan and antibiotics.•The encapsulated nanoparticles can be used to treat complicated infectious diseases.