Metallo-beta-lactamases in the periplasm: Raiders of the lost Zinc?

BARH, GUILLERMO; VILA, A J; GONZALEZ, L; GIANNINI, ESTEFANÍA; PALACIOS, ANTONELA

Queretaro

Congreso; LABIC; 2016

Metallo-beta-lactamases (MBLs) are the latestresistance mechanism of pathogenic and opportunistic bacteria againstcarbapenems, considered as last resort drugs. The worldwide spread of genescoding for these enzymes, together with the lack of a clinically usefulinhibitor, have raised a sign of alarm. Inhibitor design has been mostlyimpeded by the structural diversity of these enzymes. We have designed a seriesof inhibitors based on a common mechanism despite this diversity.Zn(II) binding is critical in the bacterialperiplasm, not only to activate these enzymes and provide resistance, but alsoto stabilize the protein scaffold. This phenomenon is not paralleled by in vitro studies. We have developed astrategy aimed to correlate the biochemical and biophysical features inpurified enzymes with those in the bacterial periplasm, ultimately leading to theselected phenotype, i.e., resistance to antibiotics. Optimization of the Zn(II)binding affinity is key in MBL evolution.Finally, we have found that in NDM, the NewDelhi Metallo-beta-lactamase, one of the most potent and widespread lactamases,membrane anchoring provides a stabilizing effect upon zinc starvationconditions, as those present during bacterial infection. This cellular localizationclaims for new drug discovery strategies, complementing enzyme inhibition.  1.      L.J. González et al. Nature ChemicalBiology 2016 12, 516.2.      P.Hinchliffe et al. Proc.Natl.Acad.Sci USA2016 111, E3745.3.      M.R. Meini et al. Mol.Biol.Evol. 2015, 32, 1774.