A new mechanism of antiobiotic resistance

16 March 2022 par Isabelle Frapart
By solving the atomic structure of the transcription factor Rho of Mycobacterium tuberculosis by cryoEM, researchers from CBM and CBS (Montpellier) have identified a mutation specifically responsible for resistance to bicyclomycin in this pathogen.

The bacterial Rho factor is a molecular motor that induces genome-wide transcription termination. Rho is essential in many species, including in Mycobacterium tuberculosis where inactivation of the rho gene leads to rapid death. Nevertheless, the Rho factor of M. tuberculosis [MtbRho] displays idiosyncrasies, including resistance to the antibiotic bicyclomycin [BCM], which remain unexplained. To identify the molecular origin of these idiosyncrasies, we solved the structure of MtbRho by cryo-EM at 3.3 Å. This atomic structure notably reveals a leucine → methionine substitution that creates steric hindrance in the binding pockets of BCM, close to the ATPase sites, thereby conferring resistance to BCM at the expanse of molecular motor efficiency. Our work contributes to explain the unusual properties of MtbRho and provides groundwork for the development of new antibiotics.

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