Antimicrobial drug-conjugates and hybrid antimicrobials

Antimicrobial drug-conjugates and hybrid antimicrobials

Bacterial resistance has to be understood as an intrinsic part of bacterial evolution. Therefore, novel antimicrobial drugs are continuously needed to counteract bacterial resistance development. Especially, Gram-negative pathogens are difficult to tackle, due to their double-layer cell wall barrier, preventing most antibiotics active against Gram-positive bacteria to enter the Gram-negative cell envelope. However, the efficient permeation barrier of the Gram-negative cell wall has some reardoors, transporters and porins which ensure the the bacteria's supply with nutrition and allows chemical communication to the enviroment.

In our lab we aim the synthesis of different antimicrobial conjugates, envisaged to enhance drug accumulation and enable translocation across the membrane barrier by utilization of these rear doors. Furthermore, we are interested into antimicrobial hybrids showing dual-targeting features to slow down the occurence of resistance.

Selected publications:

Biotransformation-coupled mutasynthesis for the generation of novel pristinamycin derivatives by engineering the phenylglycine residue, O. Hennrich, L. Weinmann, A. Kulik, K. Harms, P. Klahn, J.-W. Youn, F. Surup, Y. Mast , RCS Chem. Biol. 2023, 4, 1050-1063. DOI: 10.1039/D3CB00143A.

Design of non-cytotoxic 6,7-dihydrocoumarin-5-carboxylates with antibiofilm activity against Staphylococcus aureus and Candida albicans, R. Zscherp, A. Chakrabarti, A. P. Lehmann, H. Schrey, H. Zeng, W. Collisi, M. Stadler, P. Klahn,* Org. Biomol. Chem. 2023, 21, 4744.

Synthesis of an Antimicrobial Enterobactin-Muraymycin Conjugate for Improved Activity against Gram-negative Bacteria, C. Rohrbacher, R. Zscherp, S. C. Weck, C. Ducho*, P. Klahn*, Chem. Eur. J. 2022, e202202408, DOI: 10.1002/chem.202202408.

Advances in the synthesis of enterobactin, artificial analogues and enterobactin-derived antimicrobial drug conjugates and imaging tools for infection diagnosis, P. Klahn*, R. Zscherp, C. C. Jimidar, Synthesis 2022, DOI: 10.1055/a-1783-0751 (Invited Review article)

Biomimetic enterobactin analogue mediates iron-uptake and cargo transport into E. coli and P. aeruginosa, R. Zscherp, J. Coetzee, J. Vornweg, J. Grunenberg, J. Herrmann, R. Müller, P. Klahn*, Chem. Sci. 2021, 12, 10179-10190; ChemRxiv 2020, DOI: 10.26434/chemrxiv.13383125. (Full paper)

Enzyme-responsive nanoparticles and coatings made from alginate/peptide ciprofloxacin conjugates as drug release system, Y. Bourgat, C. Mikolai, M. Stiesch, P. Klahn, H. Menzel, Antibiotics 2021, 10, 653.

Bifunctional antimicrobial conjugates and hybrid antimicrobials, P. Klahn, M. Brönstrup, Nat. Prod. Rep. 2017, 34, 832-885.

New structural templates for clinically validated and novel targets in antimicrobial drug research and development, P. Klahn, M. Brönstrup, Curr. Top. Microbiol. Immunol. 2016, 365-417. How to Overcome the Antibiotic Crisis: Facts, Challenges, Technologies and Future Perspectives, Eds. M. Stadler, P. Dersch, Springer Verlag, 2016.)