Designing peptide amphiphiles as novel antibacterials and antibiotic adjuvants against gram-negative bacteria

Authors

Huihua Xing, University of Nebraska Medical Center
Vanessa Loya-Perez, University of Nebraska at OmahaFollow
Joshua Franzen, University of Nebraska at OmahaFollow
Paul Denton, University of Nebraska at OmahaFollow
Martin Conda-Sheridan, University of Nebraska Medical Center
Nathalia Rodrigues de Almeida, University of Nebraska at Omaha

Document Type

Article

Publication Date

9-28-2023

Publication Title

Bioorganic & Medicinal Chemistry

Volume

94

Abstract

Gram-negative strains are intrinsically resistant to most antibiotics due to the robust and impermeable characteristic of their outer membrane. Self-assembling cationic peptide amphiphiles (PAs) have the ability to disrupt bacteria membranes, constituting an excellent antibacterial alternative to small molecule drugs that can be used alone or as antibiotic adjuvants to overcome bacteria resistance. PA1 (C16KHKHK), self-assembled into micelles, which exhibited low antibacterial activity against all strains tested, and showed strong synergistic antibacterial activity in combination with Vancomycin with a Fractional Inhibitory Concentration index (FICi) of 0.15 against E. coli. The molecules, PA2 (C16KRKR) and PA3 (C16AAAKRKR), also self-assembled into micelles, displayed a broad-spectrum antibacterial activity against all strains tested, and low susceptibility to resistance development over 21 days. Finally, PA1, PA 2 and PA3 displayed low cytotoxicity against mammalian cells, and PA2 showed a potent antibacterial activity and low toxicity in preliminary in vivo models using G. mellonella. The results show that PAs are a great platform for the future development of effective antibiotics to slow down the antibiotic resistance and can act as antibiotic adjuvants with synergistic mechanism of action, which can be repurposed for use with existing antibiotics commonly used to treat gram-positive bacteria to treat infections caused by gram-negative bacteria.

Comments

This is an Accepted Manuscript of an article published by Elsevier in Bioorganic & Medicinal Chemistry on [September 28, 2023], available online: https://doi.org/10.1016/j.bmc.2023.117481

Recommended Citation

H. Xing, V. Loya-Perez, J. Franzen, P.W. Denton, M. Conda-Sheridan, N. Rodrigues de Almeida, Designing Peptide Amphiphiles as novel antibacterials and antibiotic adjuvants against Gram-negative bacteria, Bioorganic & Medicinal Chemistry (2023), doi: https://doi.org/10.1016/j.bmc.2023.117481