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6zgm

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Crystal Structure of the VIM-2 Acquired Metallo-beta-Lactamase in Complex with the thiazolecarboxylate inhibitor ANT2681

Structural highlights

6zgm is a 1 chain structure with sequence from Pseudomonas aeruginosa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.65Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q9K2N0_PSEAI

Publication Abstract from PubMed

The clinical effectiveness of the important beta-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-beta-lactamase (MBL) enzymes. To address this resistance issue, multiple beta-lactam/beta-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.

ANT2681: SAR Studies Leading to the Identification of a Metallo-beta-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.,Davies DT, Leiris S, Sprynski N, Castandet J, Lozano C, Bousquet J, Zalacain M, Vasa S, Dasari PK, Pattipati R, Vempala N, Gujjewar S, Godi S, Jallala R, Sathyap RR, Darshanoju NA, Ravu VR, Juventhala RR, Pottabathini N, Sharma S, Pothukanuri S, Holden K, Warn P, Marcoccia F, Benvenuti M, Pozzi C, Mangani S, Docquier JD, Lemonnier M, Everett M ACS Infect Dis. 2020 Aug 20. doi: 10.1021/acsinfecdis.0c00207. PMID:32786279^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Davies DT, Leiris S, Sprynski N, Castandet J, Lozano C, Bousquet J, Zalacain M, Vasa S, Dasari PK, Pattipati R, Vempala N, Gujjewar S, Godi S, Jallala R, Sathyap RR, Darshanoju NA, Ravu VR, Juventhala RR, Pottabathini N, Sharma S, Pothukanuri S, Holden K, Warn P, Marcoccia F, Benvenuti M, Pozzi C, Mangani S, Docquier JD, Lemonnier M, Everett M. ANT2681: SAR Studies Leading to the Identification of a Metallo-beta-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae. ACS Infect Dis. 2020 Aug 20. doi: 10.1021/acsinfecdis.0c00207. PMID:32786279 doi:http://dx.doi.org/10.1021/acsinfecdis.0c00207

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6zgm"

@@ Line 3: / Line 3: @@
 <StructureSection load='6zgm' size='340' side='right'caption='[[6zgm]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6zgm]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_aeruginosus"_(schroeter_1872)_trevisan_1885 "bacillus aeruginosus" (schroeter 1872) trevisan 1885]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGM OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZGM FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6zgm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZGM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZGM FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=QKK:5-[[4-(carbamimidamidocarbamoylamino)-3,5-bis(fluoranyl)phenyl]sulfonylamino]-1,3-thiazole-4-carboxylic+acid'>QKK</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.65&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">blaVIM ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=287 "Bacillus aeruginosus" (Schroeter 1872) Trevisan 1885])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=QKK:5-[[4-(carbamimidamidocarbamoylamino)-3,5-bis(fluoranyl)phenyl]sulfonylamino]-1,3-thiazole-4-carboxylic+acid'>QKK</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zgm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgm OCA], [http://pdbe.org/6zgm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zgm RCSB], [http://www.ebi.ac.uk/pdbsum/6zgm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgm 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=6zgm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zgm OCA], [https://pdbe.org/6zgm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zgm RCSB], [https://www.ebi.ac.uk/pdbsum/6zgm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zgm ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/Q9K2N0_PSEAI Q9K2N0_PSEAI]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 24: @@
 </StructureSection>
 [[Category: Large Structures]]
-[[Category: Benvenuti, M]]
+[[Category: Pseudomonas aeruginosa]]
-[[Category: Docquier, J D]]
+[[Category: Benvenuti M]]
-[[Category: Luca, F De]]
+[[Category: De Luca F]]
-[[Category: Mangani, S]]
+[[Category: Docquier JD]]
-[[Category: Marcoccia, F]]
+[[Category: Mangani S]]
-[[Category: Pozzi, C]]
+[[Category: Marcoccia F]]
-[[Category: Antibiotic resistance]]
+[[Category: Pozzi C]]
-[[Category: Carbapenem-hydrolyzing beta-lactamase]]
-[[Category: Hydrolase]]
-[[Category: Metallo-beta-lactamase]]
-[[Category: Triazole-thione inhibitor]]

6zgm

From Proteopedia

Current revision

Crystal Structure of the VIM-2 Acquired Metallo-beta-Lactamase in Complex with the thiazolecarboxylate inhibitor ANT2681

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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