Pluronic-based nano-self-assemblies of bacitracin A with a new mechanism of action for an efficient in vivo therapeutic effect against bacterial peritonitis

Although assemblies of hydrophobic-modified bacitracin A with PLGA (Nano-BAPLGA) have demonstrated promising antibacterial activities against both Gram-positive and Gram-negative bacteria, the desirable antibacterial potency has remained challenging due to the low solubility of Nano-BAPLGA. To address this tissue, a series of Pluronic copolymers (Pluronic® F127, Pluronic® P123 and Pluronic® P85) were selected to link the N-terminus of bacitracin A to construct Pluronic-based nano-self assemblies (Nano-BAF127, Nano-BAP123 and Nano-BAP85).

Collectively, the membrane targeting mechanism of action is entirely distinct from those of clinically used antibacterial agents. Furthermore, the new approach of construction nanoantibiotics based on the modification of commercially available antibiotics with Pluronic copolymers is demonstrated to have an efficient therapeutic effect against bacterial infection.

Impressively, all the newly designed Pluronic-based Nano-BAs possessed higher solubility and stronger effectiveness against both Gram-positive and Gram-negative bacteria compared with Nano-BAPLGA, especially the modification with Pluronic® P85. Surface tension measurements indicated that Nano-BAP85 was much more tensioactive than Nano-BAPLGA, which usually translated into a good membranolytic effect. Fluorescence spectroscopy and electron microscopy analyses confirmed the speculation that the cell wall/membrane might be the main action target of Nano-BAP85 by permeabilizing the cell membrane and damaging the membrane integrity. In vivo results further demonstrated that Nano-BAP85 significantly suppressed bacterial growth and prolonged survival time in the bacterial peritonitis mouse model with negligible toxicity. Conclusions: Collectively, the membrane targeting mechanism of action is entirely distinct from those of clinically used antibacterial agents. Furthermore, the new approach of construction nanoantibiotics based on the modification of commercially available antibiotics with Pluronic copolymers is demonstrated to have an efficient therapeutic effect against bacterial infection.