Antimicrobial Nanomaterials

The global spreading of antibiotic resistance is one of the greatest threats of the 21st century and can be compared to climate change in terms of its severity and effect on the world’s population. In 2019, almost 5 million deaths were associated with drug-resistant bacterial infections. At the same time, however, fewer and fewer new antibiotics are brought to market with yearly FDA approvals steadily decreasing since the 1980s. Without efficient antibiotics, many of the achievements of modern medicine that we today take for granted, such as major surgery, organ transplantation, and cancer chemotherapy, will no longer be available. Therefore, novel and unconventional approaches for the treatment of multidrug-resistant infections are urgently needed. We thus investigate and develop alternative approaches beyond the application of conventional antibiotics to combat drug-resistant bacteria and stop their spreading. In this regard, we focus in particular on the application of nanostructures and nanomaterials.

The glycopeptide antibiotic vancomycin blocks the enzymatic cross-linking of the Gram-positive cell wall by binding to the cell wall precursor peptides. Vancomycin-resistant enterococci are common hospital germs that exhibit altered peptide sequences with much lower vancomycin binding affinity. Funded by the Paderborn University Research Award 2022, we currently investigate how this reduced binding affinity can be compensated by controlled multimerization. For this purpose, dozens of vancomycin molecules are arranged in different numbers and geometries on DNA origami nanostructures and the antimicrobial activity of the multimeric vancomycin-DNA conjugates is tested in vitro on vancomycin-sensitive and vancomycin-resistant bacteria. In the next step, the DNA origami nanostructures will be functionalized further with additional antimicrobial peptides, which permeabilize the bacterial cell membrane and thus provide a second independent mechanism of action to prevent the emergence of new resistances. 

Selected publications:

• Effect of DNA Origami Nanostructures on Bacterial Growth, J.A. Garcia-Diosa, G. Grundmeier, and A. Keller, ChemBioChem 25 (2024), e202400091
• Nanoparticle-Based Formulations of Glycopeptide Antibiotics: A Means for Overcoming Vancomycin Resistance in Bacterial Pathogens? B.K. Pothineni and A. Keller, Adv. NanoBiomed Res. 3, 2200134 (2023) 

Antimicrobial photodynamic therapy is a promising alternative to classical antibiotics-based therapeutic approaches. It uses reactive oxygen species (ROS) that are generated by photosensitizers under irradiation with light of a suitable wavelength. These ROS damage surrounding cells through the non-specific oxidation of various cellular subunits, most importantly the cell membrane. While this non-specific mechanism of action makes the emergence of resistance very unlikely, it can also damage host cells. Therefore, we explore new strategies for the transport of photosensitizers directly to the bacterial cell. For this purpose, we use DNA origami nanostructures, which are loaded with established and FDA-approved photosensitizers such methylene blue and can specifically bind to the bacterial cell surface via various targeting modifications.

Press release: "Light for the treatment of tumours and bacterial infections"

Selected publications:

• Direct visualization of the drug loading of single DNA origami nanostructures by AFM-IR nanospectroscopy, M. Hanke, G. Grundmeier, and A. Keller, Nanoscale 14, 11552 (2022) (Cover Picture)
• Superstructure-Dependent Loading of DNA Origami Nanostructures with a Groove-Binding Drug, F. Kollmann, S. Ramakrishnan, B. Shen, G. Grundmeier, M.A. Kostiainen, V. Linko, and A. Keller, ACS Omega 3, 9441 (2018)

The COVID-19 pandemic has once more led to the realization that humanity is dangerously ill-prepared for fighting the threats associated with epidemic outbreaks of infectious diseases. Our basic understanding of pathogen transmission routes, which is essential for improving intervention strategies, is still insufficient. This in particular concerns fomite transmission. A fomite is any inanimate object that can be contaminated with pathogens and thereby transfer a disease from one host to another. This mechanism concerns viruses such as SARS-CoV-2 but also pathogenic bacteria and fungi and may play a dominant role in localized disease outbreaks, for instance in healthcare facilities and nursing homes. However, little is known about the physicochemical mechanisms that govern the interactions of such pathogens with abiotic surfaces and how they affect pathogen viability and infectiousness. We are thus investigating the molecular mechanisms of the adsorption and adhesion of bacterial pathogens at chemically defined model surfaces as well as the surfaces of realistic medical and everyday materials. We aim at applying the knowledge gained in these studies to the design and synthesis of antimicrobial surfaces and coatings.

Selected publications:

• Effect of Surface Hydrophobicity on the Adsorption of a Pilus-Derived Adhesin-like Peptide, Y. Yang, J. Huang, D. Dornbusch, G. Grundmeier, K. Fahmy, A. Keller, and D.L. Cheung, Langmuir 38, 9257 (2022)
• Strain-Dependent Adsorption of Pseudomonas aeruginosa-Derived Adhesin-like Peptides at Abiotic Surfaces, Y. Yang, S. Schwiderek, G. Grundmeier, and A. Keller, Micro 1, 129 (2021)