Calendario de eventos

Seminario: Novel molecular mechanisms improving fitness in zinc-dependent carbapenemases
Jueves, 21. Marzo 2019, 12:00
Contacto Juan A. Hermoso

Experto en estructura-función de proteínas, es uno de los pioneros en la aplicación de la técnica de RMN en biología estructural en Argentina. Sus temas de investigación incluyen el estudio de la resistencia bacteriana.

Metallo-beta-lactamases (MBLs) are the latest resistance mechanism of pathogenic and opportunistic bacteria against carbapenems, considered as last resort drugs. The worldwide spread of genes coding for these enzymes, together with the lack of a clinically useful inhibitor, have raised a sign of alarm. Inhibitor design has been mostly impeded by the structural diversity of these enzymes.

Zn(II) binding is critical in the bacterial periplasm, not only to activate these enzymes and provide resistance, but also to stabilize the protein scaffold. This phenomenon is not paralleled by in vitro studies. We have developed a strategy aimed to correlate the biochemical and biophysical features in purified enzymes with those in the bacterial periplasm, ultimately leading to the selected phenotype, i.e., resistance to antibiotics. We show that optimization of the Zn(II) binding affinity is key in MBL evolution, and this feature is tuned by the response of the immune system that elicits metal starvation during infection.

Finally, we have found that in NDM, the New Delhi Metallo-beta-lactamase, one of the most potent and widespread lactamases, membrane anchoring provides a stabilizing effect upon zinc starvation conditions, as those present during bacterial infection. Moreover, this cellular localization allows selective export of this enzyme into outer membrane vesicles that provide a novel mechanism to spread resistance.

 

References

L.J. González et al. Nature Chemical Biology 2016 12, 516.
Bahr et al., Antimicrob Agents Chemother. 2017;62(1). pii: e01849-17
Lisa, Palacios et al. Nature Commun. 2017, 8, 538
M.R. Meini et al. Mol.Biol.Evol. 2015, 32, 1774.

 

Fecha del seminario: 21/03/2019 12:00

Lugar del seminario: SALA 300

Ponente del seminario: Dr. Alejandro Vila

Abstract

 

Localización Sala 300 IQFR

Proyectos financiados por