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==Crystal structure of Pseudomonas aeruginosa PBP3 in complex with gamma-lactam YU253911== | ==Crystal structure of Pseudomonas aeruginosa PBP3 in complex with gamma-lactam YU253911== | ||
<StructureSection load='7lc4' size='340' side='right'caption='[[7lc4]]' scene=''> | <StructureSection load='7lc4' size='340' side='right'caption='[[7lc4]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7LC4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LC4 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7lc4]] is a 1 chain structure with sequence from [https://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=7LC4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7LC4 FirstGlance]. <br> | ||
</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=7lc4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lc4 OCA], [https://pdbe.org/7lc4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lc4 RCSB], [https://www.ebi.ac.uk/pdbsum/7lc4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lc4 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XVG:1-[(2S)-2-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-oxopropyl]-4-{[2-(5,6-dihydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]carbamoyl}-2,5-dihydro-1H-pyrazole-3-carboxylic+acid'>XVG</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">pbpB, ftsI, ftsI_2 ([https://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='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Serine-type_D-Ala-D-Ala_carboxypeptidase Serine-type D-Ala-D-Ala carboxypeptidase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.16.4 3.4.16.4] </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=7lc4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7lc4 OCA], [https://pdbe.org/7lc4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7lc4 RCSB], [https://www.ebi.ac.uk/pdbsum/7lc4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7lc4 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel gamma-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 A) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 mug/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel gamma-lactam and beta-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone. | |||
A gamma-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.,Goldberg JA, Kumar V, Spencer EJ, Hoyer D, Marshall SH, Hujer AM, Hujer KM, Bethel CR, Papp-Wallace KM, Perez F, Jacobs MR, van Duin D, Kreiswirth BN, van den Akker F, Plummer MS, Bonomo RA Eur J Med Chem. 2021 Apr 8;220:113436. doi: 10.1016/j.ejmech.2021.113436. PMID:33933754<ref>PMID:33933754</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7lc4" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Kumar V]] | [[Category: Serine-type D-Ala-D-Ala carboxypeptidase]] | ||
[[Category: | [[Category: Akker, F van den]] | ||
[[Category: Kumar, V]] | |||
[[Category: Gamma-lactam]] | |||
[[Category: Hydrolase]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Inhibitor complex]] | |||
[[Category: Pbp3]] | |||
Revision as of 13:26, 19 May 2021
Crystal structure of Pseudomonas aeruginosa PBP3 in complex with gamma-lactam YU253911Crystal structure of Pseudomonas aeruginosa PBP3 in complex with gamma-lactam YU253911
Structural highlights
Publication Abstract from PubMedSerious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel gamma-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 A) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 mug/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel gamma-lactam and beta-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone. A gamma-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.,Goldberg JA, Kumar V, Spencer EJ, Hoyer D, Marshall SH, Hujer AM, Hujer KM, Bethel CR, Papp-Wallace KM, Perez F, Jacobs MR, van Duin D, Kreiswirth BN, van den Akker F, Plummer MS, Bonomo RA Eur J Med Chem. 2021 Apr 8;220:113436. doi: 10.1016/j.ejmech.2021.113436. PMID:33933754[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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