Chemical Biology Directed to Anti-infective Drug Discovery

Our efforts to generate novel antibacterial and antiviral lead substances through chemical biology methods will be highlighted through two projects.

Infections caused by pathogenic bacteria represent a major health threat that is expected to rise further in the future. The need for novel antibiotics is currently not met by R&D efforts, in particular in the area of infections caused by Gram-negative bacteria. A main scientific hurdle is the lack of understanding how to assure a sufficient translocation of bioactive molecules across the Gram-negative cell wall. In the talk, our efforts to induce an active transport of small molecules into Gram negative bacteria and methods to quantify such uptake will be presented.

We report the design, synthesis and characterization of a series of theranostics agents based on 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid amide (DOTAM) derivatives comprising siderophores that actively target bacteria, inhibit bacterial growth and demonstrate efficacy to visualize bacterial infections in mice by optical imaging in vivo. In addition, three orthogonal approaches to detect and quantify the intracellular accumulation of such conjugates will be presented.

In the second part of the talk, a structurally intriguing natural product with broad-spectrum action against multiple human pathogenic viruses will be presented. Labyrinthopeptins are post-translationally modified peptides with lanthionine and labionine bridges that confer a largely enhanced stability in plasma compared to unmodified peptides. Following a first report on the broad anti-HIV and anti-HSV activities of LabyA1 (Férir et al. 2013), we have extended our studies to a variety of enveloped but evolutionary unrelated viruses such as Herpesviridae (HSV, CMV, KSHV), Retroviridae (HIV, RSV) or the Dengue virus (DENV). Mechanistic studies through various chemical biology techniques demonstrated that Labyrinthopeptins interact with lipidomponents of the viral surface, thereby inhibiting virus entry into target cells.