Structural Insights into Antibacterial Payload Release from Gold Nanoparticles Bound to E. coli Peptide Deformylase

Author:

Kirschner Hendrik1ORCID,John Milena2,Zhou Tianyi3,Bachmann Nathalie4,Schultz André4,Hofmann Eckhard5ORCID,Bandow Julia Elisabeth4,Scherkenbeck Jürgen3,Metzler‐Nolte Nils2ORCID,Stoll Raphael1ORCID

Affiliation:

1. Biochemistry II, Biomolecular NMR Spectroscopy RUBiospec|NMR and PhenomeCentre@RUBUAR Faculty of Chemistry and Biochemistry Ruhr University Bochum Universitätsstraße 150 44801 Bochum Germany

2. Inorganic Chemistry I – Bioinorganic Chemistry Faculty of Chemistry and Biochemistry Ruhr University Bochum Universitätsstraße 150 44801 Bochum Germany

3. Bioorganic Chemistry Faculty of Mathematics and Natural Sciences University of Wuppertal Gaußstraße 20 42119 Wuppertal Germany

4. Applied Microbiology Faculty of Biology and Biotechnology Ruhr University Bochum Universitätsstraße 150 44801 Bochum Germany

5. Protein Crystallography Faculty of Biology and Biotechnology Ruhr University Bochum Universitätsstraße 150 44801 Bochum Germany

Abstract

AbstractThe lack of new antibiotics and the rapidly rising number of pathogens resistant to antibiotics pose a serious problem to mankind. In bacteria, the cell membrane provides the first line of defence to antibiotics by preventing them from reaching their molecular target. To overcome this entrance barrier, it has been suggested[1] that small Gold‐Nanoparticles (AuNP) could possibly function as drug delivery systems for antibiotic ligands. Using actinonin‐based ligands, we provide here proof‐of‐principle of AuNP functionalisation, the capability to bind and inhibit the target protein of the ligand, and the possibility to selectively release the antimicrobial payload. To this end, we successfully synthesised AuNP coated with thio‐functionalised actinonin and a derivative. Interactions between 15N‐enriched His‐peptide deformylase 1–147 from E. coli (His‐ecPDF 1–147) and compound‐coated AuNP were investigated via 2D 1H‐15N‐HSQC NMR spectra proving the direct binding to His‐ecPDF 1–147. More importantly by adding dithiothreitol (DTT), we show that the derivative is successfully released from AuNPs while still bound to His‐ecPDF 1–147. Our findings indicate that AuNP‐conjugated ligands can address and bind intracellular target proteins. The system introduced here presents a new delivery platform for antibiotics and allows for the easy optimisation of ligand coated AuNPs.

Funder

Deutsche Forschungsgemeinschaft

European Molecular Biology Laboratory

National Institutes of Health

Publisher

Wiley

Subject

Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology

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