Sweet adhesins: Probing bacterial glycoproteins with novel tools to inspire future antibacterial strategies

Projektbeschreibung

Neue Strategien zur Infektionskontrolle

Adhäsinproteine sind bei bakteriellen Infektionen von zentraler Bedeutung. Ihre Modifikation mit hochspezifischen Zuckern scheint entscheidend für ihre Stabilität und ihre Anhaftung an Wirtszellen zu sein. In diesem Zusammenhang wird das EU-finanzierte Projekt STICKY SUGARS das Potenzial von bakteriellen Adhäsin-Zuckern für neue antibakterielle Therapien untersuchen. Gegenwärtig mangelt es an geeigneten Methoden für den direkten Nachweis von Zuckern auf Adhäsinen. Dadurch wurde die Entwicklung von antibakteriellen Strategien gegen Adhäsine bislang behindert. Das Projekt wird daher unser Verständnis von Adhäsin-Zuckern mithilfe eines innovativen Ansatzes grundlegend erweitern, indem es Kohlenhydratchemie, Enzymologie, Mikrobiologie und Molekulardynamik verknüpft. Durch die Visualisierung und Quantifizierung von Adhäsin-Zuckern direkt auf bakteriellen Oberflächen können deren Verbreitung und Reaktion auf antibakterielle Behandlungen erforscht werden, was den Weg zu einer klinischen Anwendung ebnet.

Ziel

With bacteria increasingly resistant to current antibiotics, new strategies to fight infection are needed. Bacterial adhesin proteins, which play an important role in the establishment of infection, appear to be promising targets for novel therapies. Adhesins enable the first contact between bacteria and host cells. We know that some adhesins are modified with highly unique sugars that are important for adhesin stability and adherence. However, we do not know how widespread this modification is, and whether it constitutes a good target for antibacterial strategies. A lack of suitable methods for the detection of bacterial adhesin sugars has impeded the detailed study of these sugars, blocking further efforts to develop antibacterial strategies against bacterial adhesin sugars. In this project, I aim to revolutionize our understanding of adhesin sugars, in terms of timing and prevalence of the modification, which is crucial information to start targeting adhesin sugars. To this end, I have designed an innovative approach that combines the strengths of carbohydrate chemistry, enzymology, microbiology and molecular dynamics to 1) establish straightforward methods to selectively visualize and quantify the adhesin sugars directly on the surface of bacterial cells; 2) detect the presence of adhesin sugars under changing growth conditions and in relevant clinical isolates; and 3) develop a computational method to predict the presence of sugars on adhesins that have not yet been identified. Recent findings from my team on the process of adhesin modification underscore the uniqueness of adhesin sugars, and this experience puts me in an ideal position to start this project. The overarching goal of STICKY SUGARS is to lay the foundation for the exploitation of adhesin sugars as antibacterial targets. By visualizing adhesin sugars directly on bacteria, we can observe their response to antibacterial treatments and pave the way toward clinical applications in the future.