Antibacterial agents

Our work in the antibiotics area so far has been focused on NPs with activity against Mycobacterium tuberculosis (Mtb), but  will expand to other bacterial species in the future. Our TB work was launched within the framework of the FP7 program “More Medicines for Tuberculosis (TB)” (MM4TB) (since 2011) that comprised more than 20 research groups with expertise in microbiology, cell biology, pharmacology, structural biology, screening technologies and chemistry. The FP7 program expired in 2017, but the collaborations that we established in the course of the program are still active. In the context of MM4TB we identified the bacterial NP pyridomycin as a potentially attractive lead structure for anti-TB drug discovery. While initial efforts towards the total synthesis of pyridomycin were thwarted by significant problems with the establishment of the enol ester moiety, we were able to show that the enol ester double bond in fact is not a critical requirement for antimycobacterial activity; the corresponding reduced analogs (“dihydropyridomycins”) retain most of the biological activity of the natural product, depending on the nature of the corresponding alkyl substituent and provided that the configuration of the chiral center formed in the (formal) reduction process is R. We have since investigated the SAR of dihydropyridomycins in significant detail and this work will be published in the near future.

Apart from other natural product leads, our work on Mtb has also included a broad SAR study on a new class of synthetic anti-mycobacterials that are based on a piperazine core structure.