6cfd: Difference between revisions
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<StructureSection load='6cfd' size='340' side='right' caption='[[6cfd]], [[Resolution|resolution]] 2.57Å' scene=''> | <StructureSection load='6cfd' size='340' side='right' caption='[[6cfd]], [[Resolution|resolution]] 2.57Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6cfd]] is a 14 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CFD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CFD FirstGlance]. <br> | <table><tr><td colspan='2'>[[6cfd]] is a 14 chain structure with sequence from [http://en.wikipedia.org/wiki/Atcc_19434 Atcc 19434]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CFD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CFD FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EZA:N-[(6aS,12S,15aS,17R,21R,23aS)-17,21-dimethyl-6,11,15,20,23-pentaoxooctadecahydro-2H,6H,11H,15H-pyrido[2,1-i]dipyrrolo[2,1-c 2,1-l][1,4,7,10,13]oxatetraazacyclohexadecin-12-yl]-3,5-difluoro-Nalpha-[(2E)-hept-2-enoyl]-L-phenylalaninamide'>EZA</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EZA:N-[(6aS,12S,15aS,17R,21R,23aS)-17,21-dimethyl-6,11,15,20,23-pentaoxooctadecahydro-2H,6H,11H,15H-pyrido[2,1-i]dipyrrolo[2,1-c 2,1-l][1,4,7,10,13]oxatetraazacyclohexadecin-12-yl]-3,5-difluoro-Nalpha-[(2E)-hept-2-enoyl]-L-phenylalaninamide'>EZA</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">clpP, A5804_002055, A5809_001747, A5810_000386, A5814_002098, A5836_000160, A5841_002116, A5860_002409, AS238_05290, AWT83_05460, B1P95_10385, B4W81_08585, BK413_10305, BK695_10280, BK696_10275, BTA10_07855, BTA13_11970, BU181_02235, BU182_15300, BU184_14080, BU185_04695, BU186_06175, BU187_13865, BU188_14880, BU189_03420, BU190_07525, BU191_15420, BU192_05390, BU194_04805, CDL00_11615, CKY17_04320, CKY19_04880, CQR37_09710, CQR38_04150, CQR40_12365, CQR41_03640, CQR43_09890, CRM75_14685, CRN03_11890, CS913_12780, CS915_12510, CS916_12510, DTPHA_601708, EFM1CSP_03625, HMPREF3199_00581 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1352 ATCC 19434])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Endopeptidase_Clp Endopeptidase Clp], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.92 3.4.21.92] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Endopeptidase_Clp Endopeptidase Clp], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.21.92 3.4.21.92] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6cfd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cfd OCA], [http://pdbe.org/6cfd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cfd RCSB], [http://www.ebi.ac.uk/pdbsum/6cfd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cfd ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6cfd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cfd OCA], [http://pdbe.org/6cfd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cfd RCSB], [http://www.ebi.ac.uk/pdbsum/6cfd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cfd ProSAT]</span></td></tr> | ||
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<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
Antibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been sufficiently characterized for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against both Enterococcus faecalis and Enterococcus faecium with an MIC90 of 0.016 mug/ml and 0.031 mug/ml, respectively. ClpP purified from E. faecium was found to bind ADEP4 using surface plasmon resonance analysis and ClpP activation by ADEP4 was demonstrated biochemically with a beta -casein digestion assay. In addition, E. faecium ClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In kill curves, ADEP4 was found to be bactericidal against stationary phase vancomycin resistant E. faecalis (VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 also eradicated mature VRE biofilms in combination with partnering antibiotics within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to the clinically used combinations of ampicillin and gentamicin or ampicillin and daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 co-administered with ampicillin was significantly more effective than either drug alone. These data suggest ClpP activating antibiotics may be useful for treating enterococcal infections. | |||
In vivo and in vitro effects of a ClpP activating antibiotic against vancomycin resistant enterococci.,Brown Gandt A, Griffith EC, Lister IM, Billings LL, Han A, Tangallapally R, Zhao Y, Singh AP, Lee RE, LaFleur MD Antimicrob Agents Chemother. 2018 May 21. pii: AAC.00424-18. doi:, 10.1128/AAC.00424-18. PMID:29784838<ref>PMID:29784838</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Atcc 19434]] | |||
[[Category: Endopeptidase Clp]] | [[Category: Endopeptidase Clp]] | ||
[[Category: Griffith, E C]] | [[Category: Griffith, E C]] | ||
Revision as of 09:20, 6 June 2018
ADEP4 bound to E. faecium ClpPADEP4 bound to E. faecium ClpP
Structural highlights
Function[A0A133CH35_ENTFC] Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins.[HAMAP-Rule:MF_00444][RuleBase:RU000550][SAAS:SAAS00674840] Publication Abstract from PubMedAntibiotics with novel bactericidal mechanisms of action are urgently needed. The antibiotic acyldepsipeptide 4 (ADEP4) activates the ClpP protease and causes cells to self-digest. The effects of ADEP4 and ClpP activation have not been sufficiently characterized for the enterococci, which are important pathogens known for high levels of acquired and intrinsic antibiotic resistance. In the present study, ADEP4 was found to be potently active against both Enterococcus faecalis and Enterococcus faecium with an MIC90 of 0.016 mug/ml and 0.031 mug/ml, respectively. ClpP purified from E. faecium was found to bind ADEP4 using surface plasmon resonance analysis and ClpP activation by ADEP4 was demonstrated biochemically with a beta -casein digestion assay. In addition, E. faecium ClpP was crystallized in the presence of ADEP4, revealing ADEP4 binding to ClpP in the activated state. These results confirm that the anti-enterococcal activity of ADEP4 occurs through ClpP activation. In kill curves, ADEP4 was found to be bactericidal against stationary phase vancomycin resistant E. faecalis (VRE) strain V583, and resistance development was prevented when ADEP4 was combined with multiple classes of approved antibiotics. ADEP4 also eradicated mature VRE biofilms in combination with partnering antibiotics within 72 h of treatment. Biofilm killing with ADEP4 antibiotic combinations was superior to the clinically used combinations of ampicillin and gentamicin or ampicillin and daptomycin. In a murine peritoneal septicemia model, ADEP4 alone was as effective as ampicillin. ADEP4 co-administered with ampicillin was significantly more effective than either drug alone. These data suggest ClpP activating antibiotics may be useful for treating enterococcal infections. In vivo and in vitro effects of a ClpP activating antibiotic against vancomycin resistant enterococci.,Brown Gandt A, Griffith EC, Lister IM, Billings LL, Han A, Tangallapally R, Zhao Y, Singh AP, Lee RE, LaFleur MD Antimicrob Agents Chemother. 2018 May 21. pii: AAC.00424-18. doi:, 10.1128/AAC.00424-18. PMID:29784838[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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