Vancomycin‐Modified DNA Origami Nanostructures for Targeting Bacterial Pathogens

<jats:p>The specific binding of DNA origami nanostructures (DONs) to bacteria is an important prerequisite for their application in pathogen targeting and antimicrobial drug delivery. So far, targeting bacteria with DONs has been achieved exclusively via aptamers, which suffer from drawbacks such as sensitivity toward environmental conditions and reduced binding after immobilization or conjugation. Here, an alternative approach is presented based on the modification of DONs with the cell wall‐binding glycopeptide antibiotic vancomycin. Using strain‐promoted azide‐alkyne cycloaddition, azide‐modified vancomycin is conjugated to selected staple strands and subsequently incorporated into 2D DON triangles. The resulting constructs show specific binding to the Gram‐positive species <jats:italic>Bacillus subtilis</jats:italic> (<jats:italic>B. subtilis</jats:italic>) and <jats:italic>Staphylococcus capitis</jats:italic> (<jats:italic>S. capitis</jats:italic>), and remarkably, to Gram‐negative <jats:italic>Escherichia coli</jats:italic> (<jats:italic>E. coli</jats:italic>), but no antimicrobial activity at vancomycin concentrations up to at least 2.91 μM. For <jats:italic>B. subtilis</jats:italic> and <jats:italic>E. coli</jats:italic>, DONs with vancomycin modifications on both sides exhibit better binding than DONs modified on only one side. However, both variants bind equally well to <jats:italic>S. capitis</jats:italic>. These results demonstrate the great potential of small molecule drug compounds for the robust, broad‐spectrum targeting of bacteria with DONs. Targeting a ubiquitous cell wall component of most pathogenic bacteria, vancomycin‐modified DONs have many potential applications in the prevention and treatment of nosocomial infections.</jats:p>