Structural insights into the enhanced carbapenemase efficiency of OXA-655 compared to OXA-10.

FEBS Open Bio
Hanna-Kirsti S LeirosD G Joakim Larsson

Abstract

Carbapenemases are the main cause of carbapenem resistance in Gram-negative bacteria. How β-lactamases with weak carbapenemase activity, such as the OXA-10-type class D β-lactamases, contribute to anti-bacterial drug resistance is unclear. OXA-655 is a T26M and V117L OXA-10 variant, recently identified from hospital wastewater. Despite exhibiting stronger carbapenemase activity towards ertapenem (ETP) and meropenem (MEM) in Escherichia coli, OXA-655 exhibits reduced activity towards oxyimino-substituted β-lactams like ceftazidime. Here, we have solved crystal structures of OXA-10 in complex with imipenem (IPM) and ETP, and OXA-655 in complex with MEM in order to unravel the structure-function relationship and the impact of residue 117 in enzyme catalysis. The new crystal structures show that L117 is situated at a critical position with enhanced Van der Waals interactions to L155 in the omega loop. This restricts the movements of L155 and could explain the reduced ability for OXA-655 to bind a bulky oxyimino group. The V117L replacement in OXA-655 makes the active site S67 and the carboxylated K70 more water exposed. This could affect the supply of new deacylation water molecules required for hydrolysis and possibly the carboxyl...Continue Reading

References

Jun 1, 1992·Molecular Microbiology·F CoutureR C Levesque
Oct 4, 2000·Nature Structural Biology·M PaetzelN C Strynadka
Nov 29, 2001·Proceedings of the National Academy of Sciences of the United States of America·D GolemiS Mobashery
Aug 27, 2005·Proteins·Jie LiH Bernhard Schlegel
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Sep 2, 2009·Antimicrobial Agents and Chemotherapy·Laurent PoirelPatrice Nordmann
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jun 26, 2013·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans, Garib N Murshudov
Oct 30, 2013·Antimicrobial Agents and Chemotherapy·Cynthia M JuneRachel A Powers
Jan 29, 2014·Antimicrobial Agents and Chemotherapy·Nuno T AntunesSergei B Vakulenko
Apr 4, 2014·Clinical Microbiology Reviews·Benjamin A Evans, Sebastian G B Amyes
May 6, 2015·International Journal of Molecular Sciences·Jeong Ho JeonSang Hee Lee
Jul 6, 2017·Organic & Biomolecular Chemistry·Christopher T LohansChristopher J Schofield
Aug 5, 2017·Acta Crystallographica. Section D, Structural Biology·Marta TothSergei B Vakulenko
Nov 7, 2018·Antimicrobial Agents and Chemotherapy·Stathis D KotsakisD G Joakim Larsson

❮ Previous
Next ❯

Methods Mentioned

BETA
deacylation
ion exchange chromatography
X‐ray
PISA

Software Mentioned

phenix
ExPASy
refine
Omit polder
wincoot
xds
MEM
PDBeFOLD
phaser
ProtParam

Related Concepts

Related Feeds

Carbapenems (ASM)

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.

Carbapenems

Carbapenems are members of the beta lactam class of antibiotics and are used for the treatment of severe or high-risk bacterial infections. Discover the latest research on carbapenems here.