Engineering a nanoantibiotic system displaying dual mechanism of action

In recent decades, peptide amphiphiles (PAs) have established themselves as promising self-assembling bioinspired materials in a wide range of medical fields. Herein, we report a dual-therapeutic system constituted by an antimicrobial PA and a cylindrical protease inhibitor (LJC) to achieve broad an...

Full description

Saved in:

Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 16; p. e2321498121
Main Authors:	Xing, Huihua, de Campos, Luana Janaína, Pereira, Aramis Jose, Fiora, Maria Mercedes, Aguiar-Alves, Fabio, Tagliazucchi, Mario, Conda-Sheridan, Martin
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 16-04-2024
Subjects:	Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Anti-Infective Agents Antimicrobial activity Antimicrobial agents Bacteria Biocompatibility Biological Sciences Biomimetics Cytotoxicity Effectiveness Encapsulation Fluorescence Gram-Negative Bacteria Gram-Positive Bacteria In vivo methods and tests Inoculum Larvae Membranes Microscopy Molecular theory Morphology Nanostructure Nanostructures - chemistry NMR Nuclear magnetic resonance Pharmacology Physical Sciences Polymyxin B Protease inhibitors Proteinase inhibitors Self-assembly Transmission electron microscopy antimicrobial nanostructures peptide amphiphiles dual therapy
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	In recent decades, peptide amphiphiles (PAs) have established themselves as promising self-assembling bioinspired materials in a wide range of medical fields. Herein, we report a dual-therapeutic system constituted by an antimicrobial PA and a cylindrical protease inhibitor (LJC) to achieve broad antimicrobial spectrum and to enhance therapeutic efficacy. We studied two strategies: PA-LJC nanostructures ( ) and PA nanostructures + free LJC ( ). Computational modeling using a molecular theory for amphiphile self-assembly captures and explains the morphology of PA-LJC nanostructures and the location of encapsulated LJC in agreement with transmission electron microscopy and two-dimensional (2D) NMR observations. The morphology and release profile of PA-LJC assemblies are strongly correlated to the PA:LJC ratio: high LJC loading induces an initial burst release. We then evaluated the antimicrobial activity of our nanosystems toward gram-positive and gram-negative bacteria. We found that the broadens the spectrum of LJC, reduces the therapeutic concentrations of both agents, and is not impacted by the inoculum effect. Further, the provides additional benefits including bypassing water solubility limitations of LJC and modulating the release of this molecule. The different properties of PA-LJC nanostructures results in different killing profiles, and reduced cytotoxicity and hemolytic activity. Meanwhile, details in membrane alterations caused by each strategy were revealed by various microscopy and fluorescent techniques. Last, in vivo studies in larvae treated by the strategy showed better antimicrobial efficacy than polymyxin B. Collectively, this study established a multifunctional platform using a versatile PA to act as an antibiotic, membrane-penetrating assistant, and slow-release delivery vehicle.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 1H.X. and L.J.d.C. contributed equally to this work. Edited by Monica Olvera de la Cruz, Northwestern University, Evanston, IL; received December 9, 2023; accepted March 4, 2024
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.2321498121