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Persistent URL http://purl.org/net/epubs/work/56438908
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Record Id 56438908
Title Combination of a pH-responsive peptide amphiphile and a conventional antibiotic in treating Gram-negative bacteria
Contributors
Abstract Background Clinical treatments of gastric infections using antibiotics suffer from the undesired killing of commensal bacteria and emergence of antibiotic resistance. It is desirable to develop pH responsive antimicrobial peptides (AMPs) that kill pathogenic bacteria such as H. pylori and resistant E. coli under acidic environment with minimal impact to commensal bacteria whilst not causing antibiotic resistance. Experiments Using a combined approach of cell assays, molecular dynamics (MD) simulations and membrane models facilitating biophysical and biochemical measurements including small angle neutron scattering (SANS), we have characterized the pH-responsive physiochemical properties and antimicrobial performance of two amphiphilic AMPs, GIIKDIIKDIIKDI-NH2 and GIIKKIIDDIIKKI-NH2 (denoted as 3D and 2D, respectively), that were designed by selective substitutions of cationic residues of Lys (K) in the extensively studied AMP G(IIKK)3I-NH2 with anionic residue Asp (D). Findings Whilst 2D kept non-ordered coils across the entire pH range studied, 3D displayed a range of secondary structures when pH was shifted from basic to acidic, with distinct self-assembly into nanofibers in aqueous environment. Further experimental and modeling studies revealed that the AMPs interacted differently with the inner and outer membranes of Gram-negative bacteria in a pH-responsive manner and that the structural features characterized by membrane leakage and intramembrane nanoaggregates revealed from fluorescence spectroscopy and SANS were well linked to antimicrobial actions. Different antimicrobial efficacies of 2D and 3D were underlined by the interplay between their ability to bind to the outer membrane lipid LPS (lipopolysaccharide), outer membrane permeability change and inner membrane depolarization and leakage. Furthermore, AMP’s binding with the inner membrane under acidic condition caused both the dissipation of membrane potential (Δψ) and the continuous dissipation of transmembrane ΔpH, with Δψ and ΔpH being the key components of the proton motive force. Combinations of antibiotic (Minocycline) with the pH-responsive AMP generated the synergistic effects against Gram-negative bacteria only under acidic condition. These features are crucial to target applications to gastric infections, anti-acne and wound healing.
Organisation ISIS , ISIS-SANS2D , STFC , ISIS-LARMOR
Keywords RB 2210031 , RB 2210218 , RB 1920459
Funding Information CSC, UoM-CSC joint PhD program; Industrial Collaboration Fund (R126013); Innovate UK, Knowledge Transfer Fellowship (KTP 12697); Marie Curie Fellowship ITN, Small Nano-objects for Alteration of Lipid bilayers (SNAL) (608184); BBSRC, LINK (BB/S018492/1); Innovate UK, Knowledge Transfer Partnership (KTP 10809); Innovate UK, Knowledge Transfer Partnership (KTP 11592)
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Licence Information: Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
Language English (EN)
Type Details URI(s) Local file(s) Year
Journal Article J Coll Int Sci 659 (2024): 397-412. doi:10.1016/j.jcis.2023.12.146 2024