TY - JOUR
T1 - Design, Synthesis, and Nanostructure-Dependent Antibacterial Activity of Cationic Peptide Amphiphiles
AU - Rodrigues De Almeida, Nathalia
AU - Han, Yuchun
AU - Perez, Jesus
AU - Kirkpatrick, Sydney
AU - Wang, Yilin
AU - Sheridan, Martin Conda
N1 - Funding Information:
This work was supported by Start-up funds and NIH-COBRE (5P20GM103480-Nebraska Center for Nanomedicine). We would like to thank Mohamed A. Seleem and H. Andy Zhong in the Department of Chemistry at University of Nebraska Omaha for the log P calculations in MOE software. We thank the CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Welcome Trust (UK), at The University of Queensland (Australia), for doing antimicrobial tests against bacteria and fungi, cytotoxicity against HEC-293, and hemolytic assays in human red blood cells. We would also like to express our gratitude to the Advanced Microscopy Core Facility at UNMC (Janice A. Taylor and James R. Talaska) confocal microscopy and the Flow Cytometry Research Facility at UNMC (Samantha Wall) for providing experimental assistance. The authors would like to thank Mehdi Bin Samad for providing some of the TEM images and the Electron Microscopy Core Facility (EMCF) at UNMC (Tom Bargar and Nicholas Conoan) for assistance. The EMCF is supported by the Nebraska Research Initiative (NRI), the University of Nebraska Foundation, and the Office of the Vice Chancellor for Research. The work was partially funded by the UNMC High School Alliance program with a grant from The Sherwood Foundation (MX).
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2019/1/23
Y1 - 2019/1/23
N2 - The development of bacterial resistant strains is a global health concern. Designing antibiotics that limit the rise of pathogenic resistance is essential to efficiently treat pathogenic infections. Self-assembling amphiphilic molecules are an intriguing platform for the treatment of pathogens because of their ability to disrupt bacterial membranes and function as drug nanocarriers. We have designed cationic peptide amphiphiles (PAs) that can form micelles, nanofibers, and twisted ribbons with the aim of understanding antimicrobial activity at the supramolecular level. We have found that micelle-forming PAs possess excellent antimicrobial activity against various Gram-positive and Gram-negative pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Klebsiella pneumoniae with minimal inhibitory concentrations (MICs) ranging between 1 and 8 μg/mL, when compared to nanofibers with MICs >32 μg/mL. The data suggest that the antimicrobial activity of the PAs depends on their morphology, amino acid sequence, the length of the alkyl tail, and the overall hydrophobicity of the PA. Scanning electron microscopy, confocal microscopy, and flow cytometry studies using MRSA and Escherichia coli K12 strains showed that PAs increase cell membrane permeability and disrupt the integrity of pathogen's membrane, leading to cell lysis and death. PAs are a promising platform to develop new antimicrobials that could work as nanocarriers to develop synergistic antibacterial therapies.
AB - The development of bacterial resistant strains is a global health concern. Designing antibiotics that limit the rise of pathogenic resistance is essential to efficiently treat pathogenic infections. Self-assembling amphiphilic molecules are an intriguing platform for the treatment of pathogens because of their ability to disrupt bacterial membranes and function as drug nanocarriers. We have designed cationic peptide amphiphiles (PAs) that can form micelles, nanofibers, and twisted ribbons with the aim of understanding antimicrobial activity at the supramolecular level. We have found that micelle-forming PAs possess excellent antimicrobial activity against various Gram-positive and Gram-negative pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Klebsiella pneumoniae with minimal inhibitory concentrations (MICs) ranging between 1 and 8 μg/mL, when compared to nanofibers with MICs >32 μg/mL. The data suggest that the antimicrobial activity of the PAs depends on their morphology, amino acid sequence, the length of the alkyl tail, and the overall hydrophobicity of the PA. Scanning electron microscopy, confocal microscopy, and flow cytometry studies using MRSA and Escherichia coli K12 strains showed that PAs increase cell membrane permeability and disrupt the integrity of pathogen's membrane, leading to cell lysis and death. PAs are a promising platform to develop new antimicrobials that could work as nanocarriers to develop synergistic antibacterial therapies.
KW - antimicrobials
KW - cationic nanostructures
KW - micelles
KW - peptide amphiphiles
KW - self-assembly
KW - supramolecular structure-activity relationships
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U2 - 10.1021/acsami.8b17808
DO - 10.1021/acsami.8b17808
M3 - Article
C2 - 30588791
AN - SCOPUS:85060012524
SN - 1944-8244
VL - 11
SP - 2790
EP - 2801
JO - ACS Applied Materials and Interfaces
JF - ACS Applied Materials and Interfaces
IS - 3
ER -