12-09-2017, 10:49 AM
Mycobacterium tuberculosis DNA girasa, an indispensable nanomachine involved in the regulation of DNA topology, is the only type II topoisomerase present in this organism and is therefore the sole target of the action quinolone, a crucial drug against tuberculosis multiresistant. To understand at the atomic level the mechanism of quinolone resistance that emerges in extensively drug resistant tuberculosis, functional, biophysical and structural studies were performed in combination of the two individual domains that constitute the catalytic nucleus of the DNA gyrase reaction : Toprim and domains of rupture. This allowed us to produce a catalytic reaction nuclei model in complex with DNA and a quinolone molecule, identifying the original mechanistic properties of quinolone binding and clarifying the relationships between amino acid mutations and the phenotype resistance of DNA gyrase M tuberculosis These results are consistent with our previous studies on quinolone resistance. Interestingly, the entire domain structure of the break-assembly revealed a new interaction, in which the Quinolone-Binding Pocket (QBP) is blocked by the N-terminal helix of a molecule related to symmetry. This interaction provides useful starting points for designing inhibitors based on peptides that target DNA gyrase to prevent their binding to DNA.