|
|
| (One intermediate revision not shown.) |
| Line 3: |
Line 3: |
| | <StructureSection load='7t7f' size='340' side='right'caption='[[7t7f]], [[Resolution|resolution]] 2.30Å' scene=''> | | <StructureSection load='7t7f' size='340' side='right'caption='[[7t7f]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7t7f]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T7F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T7F FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7t7f]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7T7F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7T7F FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FDX:(2R,4S)-2-(1,3-dihydroxypropan-2-yl)-4-{[(3R,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-3,4-dihydro-2H-pyrrole-5-carboxylic+acid'>FDX</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FDX:(2R,4S)-2-(1,3-dihydroxypropan-2-yl)-4-{[(3R,5R)-5-(dimethylcarbamoyl)pyrrolidin-3-yl]sulfanyl}-3,4-dihydro-2H-pyrrole-5-carboxylic+acid'>FDX</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7t7d|7t7d]]</div></td></tr>
| + | |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7t7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t7f OCA], [https://pdbe.org/7t7f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t7f RCSB], [https://www.ebi.ac.uk/pdbsum/7t7f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t7f ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7t7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7t7f OCA], [https://pdbe.org/7t7f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7t7f RCSB], [https://www.ebi.ac.uk/pdbsum/7t7f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7t7f ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | <div style="background-color:#fffaf0;">
| + | == Function == |
| - | == Publication Abstract from PubMed == | + | [https://www.uniprot.org/uniprot/V5TGX0_ACIBA V5TGX0_ACIBA] |
| - | Acinetobacter baumannii has become a major nosocomial pathogen, as it is often multidrug-resistant, which results in infections characterized by high mortality rates. The bacterium achieves high levels of resistance to beta-lactam antibiotics by producing beta-lactamases, enzymes which destroy these valuable agents. Historically, the carbapenem family of beta-lactam antibiotics have been the drugs of choice for treating A. baumannii infections. However, their effectiveness has been significantly diminished due to the pathogen's production of carbapenem-hydrolyzing class D beta-lactamases (CHDLs); thus, new antibiotics and inhibitors of these enzymes are urgently needed. Here, we describe a new carbapenem antibiotic, MA-1-206, in which the canonical C6 hydroxyethyl group has been replaced with hydroxymethyl. The antimicrobial susceptibility studies presented here demonstrated that this compound is more potent than meropenem and imipenem against A. baumannii producing OXA-23, the most prevalent CHDL of this pathogen, and also against strains producing the CHDL OXA-24/40 and the class B metallo-beta-lactamase VIM-2. Our kinetic and mass spectrometry studies revealed that this drug is a reversible inhibitor of OXA-23, where inhibition takes place through a branched pathway. X-ray crystallographic studies, molecular docking, and molecular dynamics simulations of the OXA-23-MA-1-206 complex show that the C6 hydroxymethyl group forms a hydrogen bond with the carboxylated catalytic lysine of OXA-23, effectively preventing deacylation. These results provide a promising strategy for designing a new generation of CHDL-resistant carbapenems to restore their efficacy against deadly A. baumannii infections. IMPORTANCE Carbapenem antibiotics are the drugs of choice for treatment of deadly infections caused by Gram-negative bacteria. However, their efficacy is severely compromised by the wide spread of carbapenem-hydrolyzing class D beta-lactamases (CHDLs). The importance of this research is the discovery that substitution of the canonical hydroxyethyl group of carbapenems by a hydroxymethyl significantly enhances stability against inactivation by the major CHDL of Acinetobacter baumannii, OXA-23. These results provide a novel strategy for designing next-generation, carbapenemase-stable carbapenems to fight multidrug-resistant infections caused by Gram-negative pathogens.
| + | |
| - | | + | |
| - | C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major Acinetobacter baumannii Carbapenemase OXA-23 by Impeding Deacylation.,Stewart NK, Toth M, Alqurafi MA, Chai W, Nguyen TQ, Quan P, Lee M, Buynak JD, Smith CA, Vakulenko SB mBio. 2022 Apr 14:e0036722. doi: 10.1128/mbio.00367-22. PMID:35420470<ref>PMID:35420470</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 7t7f" style="background-color:#fffaf0;"></div>
| + | |
| - | == References ==
| + | |
| - | <references/>
| + | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Acinetobacter baumannii]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Smith, C A]] | + | [[Category: Smith CA]] |
| - | [[Category: Stewart, N K]] | + | [[Category: Stewart NK]] |
| - | [[Category: Vakulenko, S B]] | + | [[Category: Vakulenko SB]] |
| - | [[Category: Antibiotic resistance]]
| + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
