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==Crystal Structure of FosB from Bacillus cereus with Zinc and 1-hydroxypropylphosphonic acid== | |||
<StructureSection load='8g7f' size='340' side='right'caption='[[8g7f]], [[Resolution|resolution]] 2.04Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8g7f]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_cereus Bacillus cereus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8G7F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8G7F FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1JJ:[(1S)-1-HYDROXYPROPYL]PHOSPHONIC+ACID'>1JJ</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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'>[https://proteopedia.org/fgij/fg.htm?mol=8g7f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8g7f OCA], [https://pdbe.org/8g7f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8g7f RCSB], [https://www.ebi.ac.uk/pdbsum/8g7f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8g7f ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/FOSB_BACC1 FOSB_BACC1] Metallothiol transferase which confers resistance to fosfomycin by catalyzing the addition of a thiol cofactor to fosfomycin. L-cysteine is probably the physiological thiol donor (By similarity). | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn(2+)-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus, one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus. Our results will inform future studies on inhibitor design for the FosB enzymes. | |||
Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus.,Travis S, Green KD, Thamban Chandrika N, Pang AH, Frantom PA, Tsodikov OV, Garneau-Tsodikova S, Thompson MK RSC Med Chem. 2023 Apr 24;14(5):947-956. doi: 10.1039/d3md00113j. eCollection , 2023 May 25. PMID:37252104<ref>PMID:37252104</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8g7f" style="background-color:#fffaf0;"></div> | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
[[Category: Travis | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Bacillus cereus]] | |||
[[Category: Large Structures]] | |||
[[Category: Garneau-Tsodikova S]] | |||
[[Category: Pang AH]] | |||
[[Category: Thompson MK]] | |||
[[Category: Travis S]] | |||
[[Category: Tsodikov OV]] | |||
Revision as of 11:19, 14 June 2023
Crystal Structure of FosB from Bacillus cereus with Zinc and 1-hydroxypropylphosphonic acidCrystal Structure of FosB from Bacillus cereus with Zinc and 1-hydroxypropylphosphonic acid
Structural highlights
FunctionFOSB_BACC1 Metallothiol transferase which confers resistance to fosfomycin by catalyzing the addition of a thiol cofactor to fosfomycin. L-cysteine is probably the physiological thiol donor (By similarity). Publication Abstract from PubMedAntimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn(2+)-dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus, one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus. Our results will inform future studies on inhibitor design for the FosB enzymes. Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus.,Travis S, Green KD, Thamban Chandrika N, Pang AH, Frantom PA, Tsodikov OV, Garneau-Tsodikova S, Thompson MK RSC Med Chem. 2023 Apr 24;14(5):947-956. doi: 10.1039/d3md00113j. eCollection , 2023 May 25. PMID:37252104[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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