Structural and Kinetic Studies of the Potent Inhibition of Metallo-β-lactamases by 6-Phosphonomethylpyridine-2-carboxylates.

Biochemistry
Philip HinchliffeGary I Dmitrienko

Abstract

There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs), enzymes that hydrolyze β-lactam antibiotics and confer resistance to Gram-negative bacteria. Here we present 6-phosphonomethylpyridine-2-carboxylates (PMPCs) as potent inhibitors of subclass B1 (IMP-1, VIM-2, and NDM-1) and B3 (L1) MBLs. Inhibition followed a competitive, slow-binding model without an isomerization step (IC50 values of 0.3-7.2 μM; Ki values of 0.03-1.5 μM). Minimum inhibitory concentration assays demonstrated potentiation of β-lactam (Meropenem) activity against MBL-producing bacteria, including clinical isolates, at concentrations at which eukaryotic cells remain viable. Crystal structures revealed unprecedented modes of binding of inhibitor to B1 (IMP-1) and B3 (L1) MBLs. In IMP-1, binding does not replace the nucleophilic hydroxide, and the PMPC carboxylate and pyridine nitrogen interact closely (2.3 and 2.7 Å, respectively) with the Zn2 ion of the binuclear metal site. The phosphonate group makes limited interactions but is 2.6 Å from the nucleophilic hydroxide. Furthermore, the presence of a water molecule interacting with the PMPC phosphonate and pyridine N-C2 π-bond, as well as the nucleophilic hydroxide, suggests that...Continue Reading

References

Jan 1, 1988·Advances in Enzymology and Related Areas of Molecular Biology·J F Morrison, C T Walsh
Oct 6, 1999·Bioorganic & Medicinal Chemistry Letters·J H ToneyD E Vanderwall
Feb 22, 2001·Antimicrobial Agents and Chemotherapy·M GalleniUNKNOWN Metallo-beta-lactamases Working Group
Feb 24, 2001·The Medical Clinics of North America·H Giamarellou, A Antoniadou
Jun 8, 2001·The Journal of Biological Chemistry·J H ToneyY D Gao
May 23, 2002·Antimicrobial Agents and Chemotherapy·David J PayneAlfonso Rivera-Sagredo
Apr 10, 2003·The Journal of Biological Chemistry·Isabel García-SaezOtto Dideberg
Dec 31, 2004·The Journal of Organic Chemistry·Mijoon LeeShahriar Mobashery
Jun 15, 2005·Biochemistry·Adriana BadarauMichael I Page
Oct 13, 2005·Journal of the American Chemical Society·James SpencerSteven J Gamblin
Feb 21, 2006·Journal of Biological Inorganic Chemistry : JBIC : a Publication of the Society of Biological Inorganic Chemistry·Alison CostelloDavid L Tierney
Aug 5, 2006·Nature Reviews. Drug Discovery·Robert A CopelandThomas D Meek
Feb 20, 2007·Antimicrobial Agents and Chemotherapy·L E HorsfallM Galleni
Jun 20, 2008·Organic & Biomolecular Chemistry·Benoît M R LiénardChristopher J Schofield
Apr 9, 2009·Biochemical and Biophysical Research Communications·Dave Gardonio, Stefan Siemann
Apr 28, 2009·The Lancet Infectious Diseases·W John LooneyKathrin Mühlemann
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Aug 29, 2009·Biochimica Et Biophysica Acta·Jennifer A JacobsenSeth M Cohen
Dec 10, 2009·Antimicrobial Agents and Chemotherapy·Karen Bush, George A Jacoby
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Vincent B ChenDavid C Richardson
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
Mar 13, 2010·The Journal of Antibiotics·Deborah M RollMay D Lee
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jun 10, 2010·Journal of Medicinal Chemistry·Patricia LassauxCarine Bebrone
Oct 5, 2010·American Journal of Respiratory and Critical Care Medicine·Valerie WatersFelix Ratjen
Oct 6, 2010·Current Opinion in Microbiology·Karen Bush
Nov 3, 2010·Journal of Chemical Information and Modeling·Haiying YuGerrit Schüürmann
Dec 7, 2010·International Journal of Antimicrobial Agents·Timothy R Walsh
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Philip R Evans
Jul 1, 2004·Biochemistry and Molecular Biology Education : a Bimonthly Publication of the International Union of Biochemistry and Molecular Biology·Marko Goliĉnik, Jure Stojan
Sep 21, 2011·Biochemistry·Dionne H GriffinMichael W Crowder

❮ Previous
Next ❯

Citations

Aug 1, 2018·International Journal of Molecular Sciences·Warawan EiamphungpornChanin Nantasenamat
Oct 24, 2018·Antimicrobial Agents and Chemotherapy·Antonela R PalaciosAlejandro J Vila
Mar 25, 2020·Antimicrobial Agents and Chemotherapy·Charlotte A SoftleyGrzegorz M Popowicz
Jun 7, 2020·Biomolecules·Antonella R PalaciosAlejandro J Vila
Oct 6, 2018·MedChemComm·Kamaleddin H M E Tehrani, Nathaniel I Martin
Nov 18, 2020·International Journal of Molecular Sciences·Corneliu Ovidiu VrancianuMariana Carmen Chifiriuc
Dec 8, 2020·Biochemistry. Biokhimii︠a︡·A M EgorovM Yu Rubtsova
Feb 23, 2021·European Journal of Medicinal Chemistry·Anka LucicChristopher J Schofield
Jul 6, 2021·European Journal of Medicinal Chemistry·Ting WangJianyou Shi
Aug 4, 2021·Colloids and Surfaces. B, Biointerfaces·Marcela Rodrigues BarrosJorge Luiz Neves
Apr 4, 2019·ACS Infectious Diseases·Nicholas J TorelliYu Chen
Sep 8, 2018·Chemical Reviews·Allie Y ChenSeth M Cohen
Sep 5, 2019·Journal of Medicinal Chemistry·Orville A PembertonYu Chen
Aug 15, 2021·European Journal of Medicinal Chemistry·Kalyan C Nagulapalli VenkataSiddharth K Tripathi
Apr 2, 2020·ACS Infectious Diseases·Kamaleddin H M E TehraniNathaniel I Martin
Nov 14, 2018·ACS Infectious Diseases·Pasquale LincianoDonatella Tondi
Aug 30, 2021·Proteins·Silvia GervasoniAdrian J Mulholland

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
PCR
Assay

Software Mentioned

Phenix
Phenix eLBOW
GraphPad
Coot
Phaser
XDS
GraphPad Prism
Molprobity
GraphPad InStat

Related Concepts

Related Feeds

Beta-lactamase Inhibitors

Beta-lactamase inhibitors are a class of antibiotics that inhibit beta-lactamases, a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. Here is the latest research.

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.

Bacterial Protein Structures

Bacterial protein structures can expedite the development of novel antibiotics. Here is the latest research on bacterial proteins and the resolution of their structures.

Beta-lactamase Inhibitors (ASM)

Beta-lactamase inhibitors are a class of antibiotics that inhibit beta-lactamases, a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. Here is the latest research.

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.

Bacterial Protein Structures (ASM)

Bacterial protein structures can expedite the development of novel antibiotics. Here is the latest research on bacterial proteins and the resolution of their structures.

© 2022 Meta ULC. All rights reserved