Novel design rules for peptide antibiotics

In light of the global ongoing pandemic, the rise of antibiotic resistance and the pipeline of novel antibiotics running dry, the discovery of novel classes of antibiotics becomes a task of primary importance. The development of novel antimicrobials is hampered by basic pharmacological challenges. Besides potential toxicity, the compound uptake into the bacterial cell represents a major obstacle.

Intracellular “resistance free” antimicrobial targets cannot be reached.Within this project the focus is on cyclic antimicrobial peptides, a promising novel class of antibiotics displaying high proteolytic stability and oral availability. Which structural feature makes cyclic AMPs permeate into cells is barely understood and will be explored in detail.

We will conduct high throughput screenings of DNA coded cyclic peptide libraries with vast structural diversity in vivo, including lanthipeptides, lasso peptides and θ-defensins.

Cyclic peptide variants will be produced by yeast cells, which will be exposed to bacterial cells, equipped with a target related intracellular biosensor, sensing peptide uptake.

Single yeast “producer cells” and bacterial “sensor cells” will be encapsulated in microdroplets and sorted via FACS.

Machine learning algorithms will be used to infer new design rules for cell permeable cyclic peptides specifically aiming at novel intracellular antimicrobial targets. Novel lead compounds will be validated through antimicrobial susceptibility testing.