Antibacterial mechanisms of action of human-targeted drugs

Advisor: Heike Brötz-Oesterhelt

Location: University of Tübingen

The microbiome is essential for human health in many different aspects. However, not only antibiotics but a variety of non-antibiotic drugs that are orally applied to treat, e.g., cardiovascular, neurological, hormonal, metabolic or other human disorders, can inhibit members of the gut microbiome as unwanted side-effects. Understanding the inhibitory effects of such human-targeted drugs (HTDs) against bacteria on a molecular level is important for separating those from the desired effects at the human targets and avoiding microbiome-disbalancing effects in the future. The current project aims to shed light on the nature of the morphological damage that HTDs inflict on bacterial cells.

For instance, the Brötz-Oesterhelt group and collaborators have recently observed that the antifungal drug clotrimazole causes membrane disorganization and inhibition of peptidoglycan synthesis in Staphylococcus aureus, forming a complex with undecaprenyl-pyrophosphate and, with lower affinity, also lipid II (Mendes et al., 2022). We also determined that the inhibitor of platelet aggregation ticagrelor targets multiple lipids in the cytoplasmic membrane of Gram-positive bacteria, disturbing membrane topology in a pleiotropic manner and destroying the membrane barrier (Leeten et al., 2024).

In the current project, we will start with the established mode of action technology of the Brötz-Oesterhelt group, based on the model organism Bacillus subtilis, which we found to be sensitive to a range of different therapeutic classes of HTDs. Interesting morphological aberrations observed in a preceding study will be analyzed further to identify the molecular target(s) and interaction partners of selected HTDs in bacterial cells. New assay technology will be established to zoom in on the potentially new target(s).

You should have completed your Master's thesis in a microbiological or biochemical subject area with excellent qualifications. High scientific interest, experimental diligence, an independent working style, a creative mind, and good communication and teamwork skills should characterize you.

References:

• Leeten et al. Ticagrelor alters the membrane of Staphylococcus aureus and enhances the activity of vancomycin and daptomycin without eliciting cross-resistance. mBio. doi: 10.1128/mbio.01322-24. (2024).
• Mendes et al. Synergetic Antimicrobial Activity and mechanism of Clotrimazole-Linked CO-Releasing Molecules. ACS Bio & Med Chem. 2:419-436 (2022)

More information about the research of Heike Brötz-Oesterhelt and a selection of recent publications can be found on her faculty page.

To apply

• Check that you meet our requirements
• Familiarize yourself with the application process and have a look at the Frequently Asked Questions
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Application deadline: 27 January 2025