Characterization of novel natural product binding sites on the DNA-gyrase of multidrug resistant Mycobacterium tuberculosis and Neisseria gonorrhoea

• Applicants: Professor Dr. Uli Kazmaier; Professor Dr. Rolf Müller; Professor Jan Rybniker, Ph.D.
• Subject Area: Pharmacy ; Biological and Biomimetic Chemistry ; Clinical Infectiology and Tropical Medicine ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology ; Structural Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545546569

In the "NaPGyr" project, German and French researchers are working on the characterization of novel drug binding sites on the bacterial DNA gyrase. Previous work has shown that the two natural product classes cystobactamides and corramycins efficiently inhibit the DNA synthesis of bacteria and thus lead to rapid cell death. The molecular targets are bacterial topoisomerases, such as DNA gyrase. Cystobactamides, which were originally isolated from myxobacteria, are accessible via total synthetic routes and more than 300 analogs of these natural products have already been synthesized in previous projects. In addition to activity data confirming the broad-spectrum effect against Gram-negative and Gram-positive bacteria, there are already data on the in vitro inhibition of gyrase and topoisomerase IV from E. coli, among others, which are inhibited in the low micromolar and nanomolar range, respectively. Due to the lack of cross-resistance to fluoroquinolones and other topoisomerase inhibitors, it can be assumed that cystobactamides address a novel binding site or inhibit bacterial topoisomerases via a novel mode of action. The same applies to corramycins, also isolated from myxobacteria, whose molecular target has not yet been elucidated; only recently the NaPGyr consortium was able to show that corramycins inhibit gyrase in Mycobacterium tuberculosis, without, however, inhibiting the gyrase. Our data point to further targets of corramycin that will also be identified within this project. Due to their relevance in the clinic, the work within NaPGyr will mainly focus on the frequently multidrug-resistant pathogens M. tuberculosis and Neisseria gonorrohoeae. The overarching goal is the comprehensive structural characterization of the presumably novel gyrase binding sites addressed by cystobactamides and corramycins. Knowledge of the molecular interactions and the mode of action will enable the design and, within this project, the synthesis of novel (and improved) derivatives that are of great interest for use as antibiotics in human therapy. On the other hand, our work significantly expands the current state of knowledge on molecules that inhibit the function of bacterial topoisomerases. The latter are targets of some of the most successful antibiotics, which is illustrated by the widespread use of fluoroquinolones and the current development of novel topoisomerase inhibitors (NBTIs such as gepotidacin).

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Dr. Stephanie Petrella