MetalZOOM February 22, 2021

Our next presentation will be:
Monday February 22 @ 10 am US Eastern Standard Time (3 pm GMT).
Alejandro Vila (IBR/Rosario, Argentina): Evolutionary features of zinc-dependent carbapenemases: A tug of war between bacteria and the immune system for the available Zn(II)

Metallo-β-lactamases (MBLs) are Zn(II)-dependent β-lactamases that constitute the latest resistance mechanism of pathogenic and opportunistic bacteria against carbapenems, considered as last resort drugs. 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. During infection, the immune system elicits a response that scavenges the available Zn(II), impacting in the activity of stability of these proteins, thus compromising bacterial survival. However, the activity and stability of these proteins in vitro does not necessarily correlate with those in the periplasm. We intend to fill the gap between in vitro and in vivo studies by means of an integrated approach. These enzymes are continuously evolving under the evolutionary pressure exerted by the indiscriminate use of antibiotics. We have studied the biochemical and biophysical features modified by the effect of accumulating mutations during evolution, both in enzymes evolved in the laboratory, as well as to study natural allelic variants selected in clinical strains. This has allowed us to account for the epistatic interactions between mutations at a structural level. We have also studied the natural evolutionary landscape of allelic variants of a clinically relevant lactamase (NDM), that has been shaped by Zn(II) deprivation
conditions. Thus, natural NDM variants with enhanced Zn(II) binding affinity have been selected, overriding the most common evolutionary pressure acting on catalytic efficiency. We also found that this enzyme is being disseminated by being secreted into Outer Membrane Vesicles, that represents an additional evolutionary advantage. Financial support from NIH, ANPCyT and CONICET is gratefully acknowledged.

References
[1] Bahr et al. Antimicrob Agents Chemother. 21;62(1) pii: e01849-17 (2017).
[2] Lisa et al. Nature Commun. 8, 53 (2017)
[3] González et al. Nature Chemical Biology, 12, 516-22 (2016).
[4] González et al. Mol.Biol. Evol., 33, 1768-76 (2016).
[5] Meini et al. Mol.Biol.Evol., 32, 1774-87 (2015).
[6] González et al. PLoS Pathogens, doi: 10.1371/journal.ppat.1003817.a (2014).
[7] González et al. Nature Chemical Biology, 8, 698-700 (2012).

Link: https://pitt.zoom.us/j/97967603148

Future seminars:
March 1: Richard Dyck (U. Calgary): What is the impact of the loss of slc30a3 (ZnT3) in mice?
March 8: Imre Lengyel (Queens U., Belfast): Title TBA
March 15: Matt Sweet (U. Queensland, Brisbane): Outzincing host defense: macrophage-mediated zinc toxicity as an antimicrobial weapon and its subversion by bacterial pathogens
March 22: Brent Stockwell (Columbia U.): New insights into GPX4 and ferroptosis through analysis of a patient variant
April 5: Thanos Tzounopoulos (U. Pittsburgh): Forms, Functions, and Mechanisms of Synaptic Zinc Signaling
April 12: Nicholas Pugh (Anglia Ruskin University, Cambridge): Zinc: an endogenous and exogenous regulator of platelet function during haemostasis and thrombosis
April 19: Ashley Bush (Florey Institute, Melbourne): Ferroptosis and Iron in Alzheimer’s disease
May 10: Kathryn Taylor (Cardiff U.): Title TBA

Past presentations (2021):
February 8: Jason Burkhead (U. Alaska, Anchorage)
February 1: Samantha Pitt (U. St. Andrews)
January 25:Wojciech Bal (Polish Academy of Sciences)
January 11: Liliana Quintanar (CINVESTAV, Mexico)

Past presentations (2020):
December 22: Jorge Busciglio (UC Irvine)
December 7: Guillermo Calero (U. Pittsburgh)
November 16: Sophie Hamleton (Newcastle U)
November 9: Amy Palmer (U Colorado, Boulder)
November 2: Blaine Roberts (Emory)
October 26: John Weiss (UC Irvine)
October 19: Klaus van Leyen (MGH/Harvard MS)
October 5: Rajiv Ratan (Burke/Cornell)
September 21: Irit Sagi (Weizmann Institute, Israel)
September 14: Fanis Missirlis (CINVESTAV, Mexico)
July 27: Math Cuajungco (UC Riverside)
July 20: Christoph Fahrni (Georgia Tech)
July 13: Carlos Aizenman (Brown)
July 6: Rachel Bainbridge (Carlson lab, Pitt)
June 29: Victor Faundez (Emory)
June 22: Eric Gaier (Harvard MS)
June 15: Essam Assali (Sekler lab, Ben Gurion U., Israel)
June 8: Moumita Chakraborty (Hershfinkel lab, Ben Gurion U., Israel)
June 1: Jahree Sosa/Kirill Kiselyov (Pitt)
May 25: Elena Sergeeva (Rosenberg lab, Harvard MS)
May 18: Yan Sun (Rotenberg lab, Harvard MS)