Matteo Dal Peraro Wins SNSF Sinergia Grant
Professor Matteo Dal Peraro at EPFL's Institute of Bioengineering (School of Life Sciences) has been awarded a Sinergia grant from the Swiss National Science Foundation (SNSF).
The SNSF Sinergia grants promote “interdisciplinary collaboration between two to four applicants whose project involves breakthrough research”. Given each year to researchers across disciplines, the Sinergia grants qualify breakthrough research as that which “calls into question or goes beyond existing models, theories, doctrines, research approaches, methods, etc.”
The project is titled “Origins of broad-spectrum β-lactam resistance: Multidimensional dissection of chromosomally encoded metallo-β-lactamases collaborators” and will be carried out together with Patrick Viollier at the University of Geneva and Juan Hermoso at the Consejo Superior de Investigaciones Científicas in Madrid, Spain.
Increasing resistance of bacterial pathogens to β-lactam antibiotics and particularly carbapenems is a major public health threat. Little is known about the underlying principles that govern the evolution of intrinsic β-lactam resistance in non-pathogenic strains from where it can be transmitted to susceptible pathogenic bacteria via mobile genetic elements. Is there a reservoir of promiscuous enzymes encoded in the genomes of environmental bacteria that can be domesticated into antibiotic-cleaving enzymes such as β-lactamases to confer intrinsic β-lactam resistance?
In this Sinergia grant we trace and recapitulate the molecular evolution of β-lactam resistance conferred by chromosomally encoded broad-spectrum metallo-β-lactamases (MBLs) that also inactivate the last resort β-lactam class of carbapenems.
Specifically, we investigate whether MBLs can (be forced to) evolve from a reservoir of general and chromosomally-encoded and zinc-dependent metallo-hydrolases of the glyoxalase GloB superfamily.
We also investigate what the intrinsic or housekeeping function of these enzymes is or might have been, reasoning that they probably cleave substrates that resemble β-lactams. Since β lactams are designed to inhibit bacterial cell wall (peptidoglycan) biosynthesis enzymes and are thus structurally similar to the peptidoglycan precursor, we will test the idea that MBLs fulfill a housekeeping role in peptidoglycan homeostasis, cleaving peptidoglycan products or similar substrates.
This work will illuminate the structure and intrinsic function of chromosomal MBLs, the principles of enzyme evolution and potential ways of gating the active site in related MBLs of pathogens, and, possibly, in all types of MBLs.