Membrane-anchoring stabilizes New Dehli carbapenemase NDM-1 upon zinc starvation and favors protein export into vesicles

GONZALEZ, L; BARH, GUILLERMO; NAKASHIGE; NOLAN; BONOMO, RA; VILA, ALEJANDRO JOSÉ

NATURE CHEMICAL BIOLOGY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2016

1552-4450

Carbapenems, ?last resort? beta-lactam antibiotics, are inactivated by zincdependentmetallo-beta-lactamases (MBLs). The host innate immune response withholdsnutrient metal ions from microbial pathogens by releasing metal-chelating proteins suchas calprotectin. We show that metal sequestration is detrimental for the accumulationof MBLs in the bacterial periplasm, since these enzymes are readily degraded in theirnon-metallated form. However, the New Delhi Metallo-beta-lactamase (NDM-1) is able topersist under conditions of metal depletion. NDM-1 is a lipidated protein anchored tothe outer membrane of Gram-negative bacteria. Membrane-anchoring contributes tothe unusual stability of NDM-1 and favors secretion of this enzyme in outer membranevesicles (OMVs). OMVs containing NDM-1 can protect nearby populations of bacteriafrom otherwise lethal antibiotic levels, and OMVs from clinical pathogens expressingNDM-1 can carry this MBL and the blaNDM gene. We show that protein export intoOMVs can be targeted, providing possibilities of new antibacterial therapeuticstrategies