Bionano Interaction Study on Antimicrobial Star-Shaped Peptide Polymer Nanoparticles

Abstract

'Structurally nanoengineered antimicrobial peptide polymers' (SNAPPs), in the form of star-shaped peptide polymer nanoparticles, have been recently demonstrated as a new class of antimicrobial agents with superior in vitro and in vivo efficacy against Gram-negative pathogens, including multidrug-resistant species. Herein, we present a detailed bionano interaction study on SNAPPs by assessing their antimicrobial activities against several Gram-negative bacteria in complex biological matrices. Simulated body fluid and animal serum were used as test media to reveal factors that influence the antimicrobial efficacy of SNAPPs. With the exception of Acinetobacter baumannii, the presence of divalent cations at physiological concentrations reduced the antimicrobial efficacy of SNAPPs from minimum inhibitory concentrations (MICs) within the nanomolar range (40-300 nM) against Escherichia coli, Pseudomanas aeruginosa, and Klebsiella pneumoniae to 0.6-4.7 μM. By using E. coli as a representative bacterial species, we demonstrated that the reduction in activity was due to a decrease in the ability of SNAPPs to cause outer and inner membrane disruption. This effect could be reversed through coadministration with a chelating agent. Interestingly, the potency of SNAPPs against A. baumannii was retained even under high salt concentrations. The presence of serum proteins was also found to affect the interaction of SNAPPs with bacterial membranes, possibly through intermolecular binding. Collectively, this study highlights the need to consider the possible interactions of (bio)molecules present in vivo with any new antimicrobial agent under development. We also demonstrate that outer membrane disruption/destabilization is an important but hitherto under-recognized target for the antimicrobial action of peptide-based agents, such as antimicrobial peptides (AMPs). Overall, the findings presented herein could aid in the design of more efficient peptide-based antimicrobial agents with uncompromised potency even under physiological conditions.

Noncytotoxic polycaprolactone-polyethyleneglycol-ε-poly(l-lysine) triblock copolymer synthesized and self-assembled as an antibacterial drug carrier

“…PCL 35 -OH (2.000 g) was dissolved in 10 mL DCM in argon atmosphere. Then, 0.842 g HDI and two drops of dibutyltion dilaurate (as catalyst) were added into the solution.…”

“…Herein, 20.000 g PEG in 40 mL of DCM was added into the PCL 35 -NCO solution, two drops of dibutyltion dilaurate were added to the mixture and reacted at room temperature for 24 h, and then the DCM was removed by rotary evaporation. The crude product was dialyzed against deionized water in a dialysis tube with 14 000 MWCO (Molecular Weight Cutoff) for 24 h (deionized water was changed every 2 h).…”

“…PCL 35 -b-PEG 45 -OH (2.000 g) was dissolved in 10 mL of DCM in a ask in an anhydrous condition. Then, 0.561 g HDI and two drops of dibutyltion dilaurate were added into the solution and stirred at 0 C for 4 h. Aer that, the crude product was precipitated in excess hexane to remove excess HDI, and the supernatant was discarded aer standing for a few minutes.…”

“…The in vitro cytotoxicity tests were conducted by culturing PCL 35 , respectively. The CCK-8 assay in Fig.…”

“…[30][31][32][33] This type of antibacterial mechanism makes it difficult for bacteria to have drug resistance to antibacterial peptides. 34,35 In addition, the antimicrobial peptides have broad spectrum and high antibacterial activity. 34,36 They have potential application as a new generation of antibiotics to solve the drugresistance problem.…”