Andre Schultz (Bochum / DE), Tianyi Zhou (Wuppertal / DE), Milena John (Bochum / DE), Pascal Dietze (Bochum / DE), Beate Menzel (Bochum / DE), Ralf Erdmann (Bochum / DE), Nils Metzler-Nolte (Bochum / DE), Jürgen Scherkenbeck (Wuppertal / DE), Julia Elisabeth Bandow (Bochum / DE)
Recent studies attributed 1.27 million deaths world-wide in 2019 to infections with multi-resistant bacteria (Murray, 2022).This emphasizes the urgency for new antibacterial agents to be developed. In this study, the utilization of small gold nanoparticles as a new drug delivery system for antibiotics was investigated. Peptide deformylase (PDF) inhibitors derived from the naturally occurring actinonin (Chen et al., 2000) were chosen as ligands for these particles (Kirschner et al., 2023). To this end, we investigated new actinonin derivates and examined the mode of action of actinonin derivative – gold nanoparticle conjugates. We screened for effective PDF inhibitors with a combination of standardized minimal inhibitory concentration assays and mass spectrometry-based analysis. For mode of action studies, gel-based proteomics was performed using the model organisms B. subtilis and E. coli. Furthermore, localization studies were performed by transmission electron microscopy.
We successfully identified derivatives with a broad activity against various gram-positive and gram-negative bacteria. The gel-based proteomics revealed that PDF is inhibited in vivo by the free actinonin derivative and the gold nanoparticle conjugate.
In localization studies it was observed that the nanoparticles did not cross the outer membrane of E. coli. Therefore, we conclude from the proteomic results, that the nanoparticles are able to deliver the antibiotic. Overall, we could show that gold nanoparticles have potential to deliver antibiotics without compromising the mode of action of their bound ligand.
Murray et al., 2022, Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet, 399:629-55
Chen et al., 2000, Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. Biochemistry, 15;39(6):1256-62
Kirschner et al., 2023, Structural insights into antibacterial payload release from gold nanoparticles bound to E. coli peptide deformylase, ChemMedChem, e202300538