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Tytuł:
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Functional Differences between E. coli and ESKAPE Pathogen GroES/GroEL.
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Autorzy:
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Sivinski J; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Ambrose AJ; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Panfilenko I; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Zerio CJ; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Machulis JM; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Mollasalehi N; Department of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona, USA.; Center for Innovation in Brain Science, Tucson, Arizona, USA.; Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, USA.
Kaneko LK; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA.
Stevens M; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Ray AM; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Park Y; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Wu C; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Hoang QQ; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.; Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Johnson SM; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Chapman E; Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA .
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Źródło:
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MBio [mBio] 2021 Jan 12; Vol. 12 (1). Date of Electronic Publication: 2021 Jan 12.
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Typ publikacji:
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Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: Washington, D.C. : American Society for Microbiology
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MeSH Terms:
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Chaperonin 10/*genetics
Chaperonin 60/*genetics
Escherichia coli/*genetics
Gram-Negative Bacteria/*genetics
Gram-Positive Bacteria/*genetics
Acinetobacter baumannii/drug effects ; Acinetobacter baumannii/genetics ; Acinetobacter baumannii/metabolism ; Anti-Bacterial Agents ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Chaperonin 10/chemistry ; Chaperonin 10/metabolism ; Chaperonin 60/chemistry ; Chaperonin 60/metabolism ; Enterobacter/drug effects ; Enterobacter/genetics ; Enterobacter/metabolism ; Enterococcus faecium/drug effects ; Enterococcus faecium/genetics ; Enterococcus faecium/metabolism ; Escherichia coli/drug effects ; Escherichia coli/metabolism ; Gene Knock-In Techniques ; Gene Knockout Techniques ; Gram-Negative Bacteria/drug effects ; Gram-Negative Bacteria/metabolism ; Gram-Positive Bacteria/drug effects ; Gram-Positive Bacteria/metabolism ; Kinetics ; Klebsiella pneumoniae/drug effects ; Klebsiella pneumoniae/genetics ; Klebsiella pneumoniae/metabolism ; Pseudomonas aeruginosa/drug effects ; Pseudomonas aeruginosa/genetics ; Pseudomonas aeruginosa/metabolism ; Staphylococcus aureus/drug effects ; Staphylococcus aureus/genetics ; Staphylococcus aureus/metabolism
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Grant Information:
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P30 ES006694 United States ES NIEHS NIH HHS; T32 GM008804 United States GM NIGMS NIH HHS; R01 GM115844 United States GM NIGMS NIH HHS; R01 GM120350 United States GM NIGMS NIH HHS; R01 GM111639 United States GM NIGMS NIH HHS
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Contributed Indexing:
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Keywords: ESKAPE; GroEL; GroES; HSP10; HSP60; antibiotic; antimicrobial; chaperone; chaperonin
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Substance Nomenclature:
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0 (Anti-Bacterial Agents)
0 (Bacterial Proteins)
0 (Chaperonin 10)
0 (Chaperonin 60)
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Entry Date(s):
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Date Created: 20210113 Date Completed: 20210907 Latest Revision: 20211111
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Update Code:
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20240105
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PubMed Central ID:
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PMC7844535
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DOI:
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10.1128/mBio.02167-20
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PMID:
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33436430
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As the GroES/GroEL chaperonin system is the only bacterial chaperone that is essential under all conditions, we have been interested in the development of GroES/GroEL inhibitors as potential antibiotics. Using Escherichia coli GroES/GroEL as a surrogate, we have discovered several classes of GroES/GroEL inhibitors that show potent antibacterial activity against both Gram-positive and Gram-negative bacteria. However, it remains unknown if E. coli GroES/GroEL is functionally identical to other GroES/GroEL chaperonins and hence if our inhibitors will function against other chaperonins. Herein we report our initial efforts to characterize the GroES/GroEL chaperonins from clinically significant ESKAPE pathogens ( Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species). We used complementation experiments in GroES/GroEL-deficient and -null E. coli strains to report on exogenous ESKAPE chaperone function. In GroES/GroEL-deficient (but not knocked-out) E. coli , we found that only a subset of the ESKAPE GroES/GroEL chaperone systems could complement to produce a viable organism. Surprisingly, GroES/GroEL chaperone systems from two of the ESKAPE pathogens were found to complement in E. coli , but only in the strict absence of either E. coli GroEL ( P. aeruginosa ) or both E. coli GroES and GroEL ( E. faecium ). In addition, GroES/GroEL from S. aureus was unable to complement E. coli GroES/GroEL under all conditions. The resulting viable strains, in which E. coli groESL was replaced with ESKAPE groESL , demonstrated similar growth kinetics to wild-type E. coli , but displayed an elongated phenotype (potentially indicating compromised GroEL function) at some temperatures. These results suggest functional differences between GroES/GroEL chaperonins despite high conservation of amino acid identity. IMPORTANCE The GroES/GroEL chaperonin from E. coli has long served as the model system for other chaperonins. This assumption seemed valid because of the high conservation between the chaperonins. It was, therefore, shocking to discover ESKAPE pathogen GroES/GroEL formed mixed-complex chaperonins in the presence of E. coli GroES/GroEL, leading to loss of organism viability in some cases. Complete replacement of E. coli groESL with ESKAPE groESL restored organism viability, but produced an elongated phenotype, suggesting differences in chaperonin function, including client specificity and/or refolding cycle rates. These data offer important mechanistic insight into these remarkable machines, and the new strains developed allow for the synthesis of homogeneous chaperonins for biochemical studies and to further our efforts to develop chaperonin-targeted antibiotics.
(Copyright © 2021 Sivinski et al.)