Novel actinobacterial TrmD inhibitors to combat Gram-negative pathogens

• Applicant: Dr. Chantal Bader
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 501989175

With the spread of multi-drug resistances, infectious diseases have become a major threat to the global health system again and discovery of unprecedented anti-infectives with novel mode of action is urgently needed. The methyltransferase TrmD represents a promising new target for the development of anti-Gram-negative antibiotics being responsible for methylation of the tRNA and therefore crucial for correct protein biosynthesis, especially when it comes to membrane protein synthesis. Medicinal chemistry approaches have already identified TrmD inhibitors with excellent protein affinities, which however suffer from poor cell permeability and therefore are not suitable as drug candidates. We now aim to identify natural products (NPs) inhibiting TrmD, which allows us to discover anti-Gram-negative antibiotics with evolutionary optimized pharmacokinetic and pharmacodynamic properties. Therefore, the 74,777-member NP library of extracts and fractions at the Scripps Research Institute is currently being screened in the Shen lab, utilizing an Escherichia coli tolC+ cell-based dual assay. This proposed project will focus on subsequent dereplication, isolation, and structural characterization of the top five hits generated in this screening. Native mass spectrometry, as state-of-the-art analytical technique, will help to identify TrmD-targeting NPs in the complex actinobacterial extracts, and genome sequencing of the hit strains will be used to identify the biosynthetic gene clusters encoding the active NPs and potential resistance genes of the producers. Once the pure NPs are in hand, we will assess their potential as next-generation antibiotics targeting Gram-negative bacteria using a broader panel of pathogens. Furthermore, we will choose one of the new NPs for in depth-analysis of its biosynthetic origin, setting the stage to engineer designer analogues, with improved in vivo activity, by synthetic biology strategies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Ben Shen, Ph.D.