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

Huihua Xing; Vanessa Loya-Perez; Joshua Franzen; Paul W Denton; Martin Conda-Sheridan; Nathalia Rodrigues de Almeida

doi:10.1016/j.bmc.2023.117481

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

Bioorg Med Chem. 2023 Oct 30:94:117481. doi: 10.1016/j.bmc.2023.117481. Epub 2023 Sep 20.

Authors

Huihua Xing¹, Vanessa Loya-Perez², Joshua Franzen³, Paul W Denton³, Martin Conda-Sheridan¹, Nathalia Rodrigues de Almeida⁴

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States.
² Department of Chemistry, University of Nebraska Omaha, Omaha, NE 68182, United States.
³ Department of Biology, University of Nebraska Omaha, Omaha, NE 68182, United States.
⁴ Department of Chemistry, University of Nebraska Omaha, Omaha, NE 68182, United States. Electronic address: nalmeida@trinity.edu.

PMID: 37776750
DOI: 10.1016/j.bmc.2023.117481

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.