Caractérisation de nouveaux sites de liaison de produits naturels sur l’ADN gyrase de souches multirésistantes aux antibiotiques de Mycobacterium tuberculosis et Neisseria gonorrhoea – NaPGyr

In the “NaPGyr” project, German and French researchers are working on the characterization of novel drug binding sites on bacterial DNA gyrase. Previous work has shown that the two classes of natural products cystobactamides and corramycins efficiently inhibit DNA synthesis in bacteria and thus lead to rapid cell death. The molecular target is bacterial topoisomerases, such as DNA gyrase. Cystobactamides, which were originally isolated from myxobacteria, are accessible via total synthetic routes and in previous projects more than 300 analogues of these natural products have already been synthesized. In addition to activity data that confirm the broad-spectrum effect against Gram-negative and Gram-positive bacteria, there are already data on the in vitro inhibition of, among other things, gyrase and topoisomerase IV from E. coli, which are inhibited in the low micromolar and nanomolar ranges, 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 the bacterial topoisomerases via a novel mechanism of action. The same applies to the corramycins, which were also isolated from myxobacteria and whose molecular target has not yet been elucidated; The NaPGyr consortium was only recently able to show that corramycins particularly inhibit gyrase in Mycobacterium tuberculosis, but without showing cross-resistance with fluoroquinolones. Our data indicate additional targets of corramycin that will also be identified within this project. Due to their relevance in the clinic, the work within NaPGyr will focus primarily on the often multi-resistant pathogens M. tuberculosis and Neisseria gonorrohoeae. The overall goal here is the comprehensive structural characterization of the presumably novel gyrase binding sites that are addressed by cystobactamids and corramycins. Knowledge of the molecular interactions and the mechanism 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 knowledge of molecules that inhibit the function of bacterial topoisomerases. The latter are targets of some of the most successful antibiotics, as illustrated by the widespread use of fluoroquinolones and the current development of novel topoisomerase inhibitors (NBTIs such as gepotidacin).