NXL104 irreversibly inhibits the β-lactamase from Mycobacterium tuberculosis.

Biochemistry
Hua XuJohn S Blanchard

Abstract

NXL104 is a novel β-lactamase inhibitor with a non-lactam structural scaffold. Our kinetic and mass spectrometric analysis demonstrates that NXL104 quantitatively inhibits BlaC, the only chromosomally encoded β-lactamase from Mycobacterium tuberculosis, by forming a carbamyl adduct with the enzyme. The inhibition efficiency (k(2)/K) of NXL104 was shown to be more than 100-fold lower than that of clavulanate, a classical β-lactamase inhibitor, which is probably caused by the bulky rings of NXL104. However, the decarbamylation rate constant (k(3)) was determined to be close to zero. The BlaC-NXL104 adduct remained stable for at least 48 h, while the hydrolysis of the BlaC-clavulanate adduct was observed after 2 days. The three-dimensional crystal structure of the BlaC--NXL104 carbamyl adduct was determined at a resolution of 2.3 Å. Interestingly, the sulfate group of NXL104 occupies the position of a phosphate ion in the structure of the BlaC-clavulanate adduct and is hydrogen bonded to residues Ser128, Thr237, and Thr239. Favorable interactions are also seen in the electrostatic potential map. We propose that these additional interactions, as well as the intrinsic stability of the carbamyl linkage, contribute to the extraordinar...Continue Reading

References

Dec 5, 1998·Microbiology and Molecular Biology Reviews : MMBR·C Goffin, J M Ghuysen
Mar 25, 1999·Acta Crystallographica. Section D, Biological Crystallography·N S PannuR J Read
Jul 2, 2003·Acta Crystallographica. Section D, Biological Crystallography·Elizabeth PottertonEleanor Dodson
Jul 16, 2004·The Journal of Antimicrobial Chemotherapy·Alain BonnefoyMaxime Lampilas
May 1, 1997·Acta Crystallographica. Section D, Biological Crystallography·G N MurshudovE J Dodson
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
May 6, 2005·The Journal of Antimicrobial Chemotherapy·Barry G Hall, Miriam Barlow
Oct 6, 2007·Biochemistry·Jean-Emmanuel Hugonnet, John S Blanchard
Dec 27, 2007·The Canadian Journal of Infectious Diseases & Medical Microbiology = Journal Canadien Des Maladies Infectieuses Et De La Microbiologie Médicale·L E Nicolle, UNKNOWN AMMI Canada Guidelines Committee*
Aug 12, 2008·The Journal of Antimicrobial Chemotherapy·David M LivermoreNeil Woodford
Jul 1, 1946·The Journal of Pathology and Bacteriology·C N ILAND
Oct 6, 2010·Antimicrobial Agents and Chemotherapy·Thérèse StachyraMichael T Black
Aug 13, 2011·Bulletin of the World Health Organization·Philippe GlaziouMario Raviglione
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

❮ Previous
Next ❯

Citations

Jul 9, 2013·Expert Opinion on Drug Discovery·Michio KurosuKatsuhiko Mitachi
Mar 24, 2016·Angewandte Chemie·Mathieu F ChellatRainer Riedl
Apr 10, 2015·ACS Infectious Diseases·Dustin T KingNatalie C J Strynadka
Apr 5, 2016·Expert Review of Anti-infective Therapy·Bradley J Gardiner, Yoav Golan
Dec 20, 2014·The Journal of Antimicrobial Chemotherapy·Vincent DubéeMichel Arthur
May 22, 2016·Infectious Disease Clinics of North America·Krisztina M Papp-Wallace, Robert A Bonomo
Jan 1, 2014·Antimicrobial Agents and Chemotherapy·Sarah M DrawzRobert A Bonomo
Dec 2, 2015·Antimicrobial Agents and Chemotherapy·Diansy ZinckeKalai Mathee
Jul 8, 2015·Antimicrobial Agents and Chemotherapy·Daria SorokaMichel Arthur
Feb 21, 2019·Antimicrobial Agents and Chemotherapy·Chand S MangatBrian L Mark
Dec 25, 2019·Antimicrobial Agents and Chemotherapy·Wouter ElingsMarcellus Ubbink
Aug 7, 2019·Antimicrobial Agents and Chemotherapy·Catherine L TookeJames Spencer
Apr 15, 2020·Chemistry : a European Journal·Chandan Kumar Das, Nisanth N Nair
Sep 20, 2017·The Journal of Antimicrobial Chemotherapy·Devyani DeshpandeTawanda Gumbo
Jul 5, 2019·International Journal of Molecular Sciences·Timothy W MouralClifford E Berkman
Mar 4, 2020·Proceedings of the National Academy of Sciences of the United States of America·Orville A PembertonYu Chen
Aug 6, 2013·The Journal of Biological Chemistry·David E EhmannStewart L Fisher
Jan 1, 2017·The Journal of Antimicrobial Chemotherapy·Daria SorokaMichel Arthur
Dec 25, 2019·International Journal of Biological Macromolecules·Sourya BhattacharyaSaugata Hazra
Feb 15, 2021·International Journal of Biological Macromolecules·Sourya BhattacharyaSaugata Hazra
Jan 5, 2021·ACS Infectious Diseases·Nichole K StewartSergei B Vakulenko

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antitubercular Agents (ASM)

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.

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.

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.

Antitubercular Agents

Antitubercular agents are pharmacologic agents for treatment of tuberculosis. Discover the latest research on antitubercular agents here.