Minocycline and Silver Dual-Loaded Polyphosphoester-Based Nanoparticles for Treatment of Resistant Pseudomonas aeruginosa.
Qingquan ChenKush N ShahFuwu ZhangAdam J SalazarParth N ShahRichen LiJames C SacchettiniKaren L WooleyCarolyn L CannonPublished in: Molecular pharmaceutics (2019)
Pseudomonas aeruginosa has been detected in the lungs of ∼50% of patients with cystic fibrosis (CF), including 20% of adult CF patients. The majority of these adult patients harbor multi-drug resistant (MDR) strains, limiting the available treatment options. Silver has long been used as a broad-spectrum antimicrobial agent with a low incidence of resistance. Despite low toxicity, poor availability of silver cations mandates a high dosage to effectively eradicate infections. To address this shortcoming of silver, nanoparticles have been used as delivery devices to improve treatment outcomes. Furthermore, studies have demonstrated that synergistic combinations with careful dose calibrations and efficient delivery systems result in superior antimicrobial activity while avoiding potential side effects of both therapeutics. Here 4-epi-minocycline, a metabolite of minocycline, was identified as an active antimicrobial against P. aeruginosa using a high-throughput screen. The antimicrobial activities of 4-epi-minocycline, minocycline, and silver acetate against clinical isolates of P. aeruginosa obtained from CF patients were evaluated in vitro. Next, the synergistic activity of the silver/minocycline combination against P. aeruginosa isolates was investigated using checkerboard assays and identified with end-point colony forming unit determination assays. Finally, nanoparticles coloaded with minocycline and silver were evaluated in vitro for antimicrobial activity. The results demonstrated that both silver and minocycline are potent antimicrobials alone and that the combination allows a reduced dosage of both therapeutics to achieve the same antimicrobial effect. Furthermore, the proposed synergistic silver/minocycline combination can be coloaded into nanoparticles as a next-generation antibiotic to combat the threats presented by MDR pathogens.
Keyphrases
- silver nanoparticles
- gold nanoparticles
- high throughput
- drug resistant
- pseudomonas aeruginosa
- cystic fibrosis
- end stage renal disease
- staphylococcus aureus
- ejection fraction
- multidrug resistant
- newly diagnosed
- cancer therapy
- small molecule
- oxidative stress
- drug delivery
- risk factors
- mass spectrometry
- biofilm formation
- single cell
- risk assessment
- candida albicans
- high resolution
- smoking cessation