Search Menu
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information
Search Scholarly Publications

Title: Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase

Abstract

We report a series of six novel metallocenyl-7-ADCA (metallocenyl = ferrocenyl or ruthenocenyl; 7-ADCA = 7- aminodesacetoxycephalosporanic acid) conjugates were synthesized and their antibacterial properties evaluated by biochemical and microbiological assays. The ruthenocene derivatives showed a higher level of inhibition of DDcarboxypeptidase 64-575, a penicillin binding protein (PBP), than the ferrocene derivatives and the reference compound penicillin G. Protein X-ray crystallographic analysis revealed a covalent acyl–enzyme complex of a ruthenocenyl compound with CTX-M β-lactamase E166A mutant, corresponding to a similar complex with PBPs responsible for the bactericidal activities of these compounds. Most interestingly, an intact compound was captured at the crystal-packing interface, elucidating for the first time the structure of a metallocenyl β-lactam compound that previously eluded small-molecule crystallography. We propose that protein crystals, even from biologically unrelated molecules, can be utilized to determine structures of small molecules.

Authors:
 [1];  [2];  [1];  [2];  [3];  [3]; ORCiD logo [4];  [2]; ORCiD logo [1]
+ Show Author Affiliations
  1. Univ. of South Florida, Tampa, FL (United States). Morsani College of Medicine
  2. Univ. of Łódź, Tamka (Poland)
  3. National Inst. of Public Health - National Inst. of Hygiene (NIPH-NIH), Warsaw (Poland)
  4. Univ. of Zagreb (Croatia)
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); National Science Centre of Poland (NCN)
OSTI Identifier:
1463718
Grant/Contract Number:  
DEC-2013/11/B/ ST5/00997
Resource Type:
Accepted Manuscript
Journal Name:
Organometallics
Additional Journal Information:
Journal Volume: 36; Journal Issue: 9; Journal ID: ISSN 0276-7333
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Crystals; Antimicrobial agents; Peptides and proteins; Monomers; Crystal structure

Citation Formats

Lewandowski, Eric M., Szczupak, Łukasz, Wong, Stephanie, Skiba, Joanna, Guśpiel, Adam, Solecka, Jolanta, Vrček, Valerije, Kowalski, Konrad, and Chen, Yu. Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase. United States: N. p., 2017. Web. doi:10.1021/acs.organomet.6b00888.
Copy to clipboard
Lewandowski, Eric M., Szczupak, Łukasz, Wong, Stephanie, Skiba, Joanna, Guśpiel, Adam, Solecka, Jolanta, Vrček, Valerije, Kowalski, Konrad, & Chen, Yu. Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase. United States. https://doi.org/10.1021/acs.organomet.6b00888
Copy to clipboard
Lewandowski, Eric M., Szczupak, Łukasz, Wong, Stephanie, Skiba, Joanna, Guśpiel, Adam, Solecka, Jolanta, Vrček, Valerije, Kowalski, Konrad, and Chen, Yu. Wed . "Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase". United States. https://doi.org/10.1021/acs.organomet.6b00888. https://www.osti.gov/servlets/purl/1463718.
Copy to clipboard
@article{osti_1463718,
title = {Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase},
author = {Lewandowski, Eric M. and Szczupak, Łukasz and Wong, Stephanie and Skiba, Joanna and Guśpiel, Adam and Solecka, Jolanta and Vrček, Valerije and Kowalski, Konrad and Chen, Yu},
abstractNote = {We report a series of six novel metallocenyl-7-ADCA (metallocenyl = ferrocenyl or ruthenocenyl; 7-ADCA = 7- aminodesacetoxycephalosporanic acid) conjugates were synthesized and their antibacterial properties evaluated by biochemical and microbiological assays. The ruthenocene derivatives showed a higher level of inhibition of DDcarboxypeptidase 64-575, a penicillin binding protein (PBP), than the ferrocene derivatives and the reference compound penicillin G. Protein X-ray crystallographic analysis revealed a covalent acyl–enzyme complex of a ruthenocenyl compound with CTX-M β-lactamase E166A mutant, corresponding to a similar complex with PBPs responsible for the bactericidal activities of these compounds. Most interestingly, an intact compound was captured at the crystal-packing interface, elucidating for the first time the structure of a metallocenyl β-lactam compound that previously eluded small-molecule crystallography. We propose that protein crystals, even from biologically unrelated molecules, can be utilized to determine structures of small molecules.},
doi = {10.1021/acs.organomet.6b00888},
journal = {Organometallics},
number = 9,
volume = 36,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2017},
month = {Wed Feb 01 00:00:00 EST 2017}
}
Copy to clipboard
Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/acs.organomet.6b00888
Copyright Statement
Other availability
Search WorldCat Search WorldCat to find libraries that may hold this journal
Citation Metrics:
Cited by: 36 works
Citation information provided by
Web of Science
Save / Share:
Export Metadata
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.

Works referenced in this record:

beta-Lactamases in laboratory and clinical resistance.
journal, October 1995

Atomic Resolution Structures of CTX-M β-Lactamases: Extended Spectrum Activities from Increased Mobility and Decreased Stability
journal, April 2005

Zinc as a Cofactor for Cephalosporinase from Bacillus cereus 569
journal, January 1966

  • Sabath, L. D.; Abraham, E. P.
  • Biochemical Journal, Vol. 98, Issue 1
  • DOI: 10.1042/bj0980011C

Molecular Basis for the Catalytic Specificity of the CTX-M Extended-Spectrum β-Lactamases
journal, December 2014

  • Adamski, Carolyn J.; Cardenas, Ana Maria; Brown, Nicholas G.
  • Biochemistry, Vol. 54, Issue 2
  • DOI: 10.1021/bi501195g

Structural Analysis of the Role of Pseudomonas aeruginosa Penicillin-Binding Protein 5 in β-Lactam Resistance
journal, April 2013

  • Smith, Jeffrey D.; Kumarasiri, Malika; Zhang, Weilie
  • Antimicrobial Agents and Chemotherapy, Vol. 57, Issue 7
  • DOI: 10.1128/AAC.00505-13

Enzyme crystal structure in a neat organic solvent.
journal, September 1993

  • Fitzpatrick, P. A.; Steinmetz, A. C.; Ringe, D.
  • Proceedings of the National Academy of Sciences, Vol. 90, Issue 18
  • DOI: 10.1073/pnas.90.18.8653

Intermolecular hydrogen bonds with d-electrons of transition metal atoms. H-complexes with metallocenes of the iron subgroup
journal, December 1993

Distinct Single-Cell Morphological Dynamics under Beta-Lactam Antibiotics
journal, December 2012

Locating interaction sites on proteins: The crystal structure of thermolysin soaked in 2% to 100% isopropanol
journal, December 1999

A new class of semi-synthetic antibiotics: ferrocenyl-penicillins and -cephalosporins
journal, March 1976

Challenges and Opportunities in the Development of Organometallic Anticancer Drugs
journal, July 2012

  • Hartinger, Christian G.; Metzler-Nolte, Nils; Dyson, Paul J.
  • Organometallics, Vol. 31, Issue 16
  • DOI: 10.1021/om300373t

The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis
journal, March 2008

Three Decades of  -Lactamase Inhibitors
journal, January 2010

  • Drawz, S. M.; Bonomo, R. A.
  • Clinical Microbiology Reviews, Vol. 23, Issue 1
  • DOI: 10.1128/CMR.00037-09

The future of the β-lactams
journal, October 2010

  • Llarrull, Leticia I.; Testero, Sebastian A.; Fisher, Jed F.
  • Current Opinion in Microbiology, Vol. 13, Issue 5
  • DOI: 10.1016/j.mib.2010.09.008

Hydrogen-bonded complexes involving the metal atom and protonation of metallocenes of the iron subgroup
journal, February 1994

  • Shubina, E. S.; Krylov, A. N.; Kreindlin, A. Z.
  • Journal of Organometallic Chemistry, Vol. 465, Issue 1-2
  • DOI: 10.1016/0022-328X(94)87063-2

The Bacteria Fight Back
journal, July 2008

Synthesis and Biological Evaluation of Ferrocene-Containing Bioorganometallics Inspired by the Antibiotic Platensimycin Lead Structure
journal, October 2010

  • Patra, Malay; Gasser, Gilles; Wenzel, Michaela
  • Organometallics, Vol. 29, Issue 19
  • DOI: 10.1021/om100614c

X-ray analysis on the nanogram to microgram scale using porous complexes
journal, March 2013

  • Inokuma, Yasuhide; Yoshioka, Shota; Ariyoshi, Junko
  • Nature, Vol. 495, Issue 7442
  • DOI: 10.1038/nature11990

Ferrocifen type anti cancer drugs
journal, January 2015

  • Jaouen, Gérard; Vessières, Anne; Top, Siden
  • Chemical Society Reviews, Vol. 44, Issue 24
  • DOI: 10.1039/C5CS00486A

Resistance to antibiotics targeted to the bacterial cell wall: The Bacterial Cell Wall as a Target for Antibiotics
journal, January 2014

  • Nikolaidis, I.; Favini-Stabile, S.; Dessen, A.
  • Protein Science, Vol. 23, Issue 3
  • DOI: 10.1002/pro.2414

Ferrocenyl bioconjugates of ampicillin and 6-aminopenicillinic acid – Synthesis, electrochemistry and biological activity
journal, November 2012

  • Skiba, Joanna; Rajnisz, Aleksandra; de Oliveira, Kely Navakoski
  • European Journal of Medicinal Chemistry, Vol. 57
  • DOI: 10.1016/j.ejmech.2012.09.023

Small organometallic compounds as antibacterial agents
journal, January 2012

  • Patra, Malay; Gasser, Gilles; Metzler-Nolte, Nils
  • Dalton Transactions, Vol. 41, Issue 21
  • DOI: 10.1039/c2dt12460b

Metallocene-Modified Uracils: Synthesis, Structure, and Biological Activity
journal, May 2013

  • Kowalski, Konrad; Skiba, Joanna; Oehninger, Luciano
  • Organometallics, Vol. 32, Issue 20
  • DOI: 10.1021/om400294s

Epidemiological Expansion, Structural Studies, and Clinical Challenges of New β-Lactamases from Gram-Negative Bacteria
journal, October 2011

Getting to the route of Helicobacter pylori treatment
journal, July 1998

  • Goddard, A.
  • Journal of Antimicrobial Chemotherapy, Vol. 42, Issue 1
  • DOI: 10.1093/jac/42.1.1

Growing Group of Extended-Spectrum  -Lactamases: the CTX-M Enzymes
journal, December 2003

Intermolecular Cross Linking of a Protein in the Crystalline State: Carboxypeptidase-A
journal, September 1964

  • Quiocho, F. A.; Richards, F. M.
  • Proceedings of the National Academy of Sciences, Vol. 52, Issue 3
  • DOI: 10.1073/pnas.52.3.833

Multiple Solvent Crystal Structures: Probing Binding Sites, Plasticity and Hydration
journal, April 2006

  • Mattos, Carla; Bellamacina, Cornelia R.; Peisach, Ezra
  • Journal of Molecular Biology, Vol. 357, Issue 5
  • DOI: 10.1016/j.jmb.2006.01.039

Highly active antibacterial ferrocenoylated or ruthenocenoylated Arg-Trp peptides can be discovered by an l -to- d substitution scan
journal, January 2014

  • Albada, H. Bauke; Prochnow, Pascal; Bobersky, Sandra
  • Chem. Sci., Vol. 5, Issue 11
  • DOI: 10.1039/C4SC01822B

Metallo-β-lactamase structure and function: Metallo-β-lactamase structure and function
journal, November 2012

Separation, purification and properties of β-lactamase I and β-lactamase II from Bacillus cereus 569/H/9
journal, October 1974

  • Davies, Richard B.; Abraham, E. P.; Melling, J.
  • Biochemical Journal, Vol. 143, Issue 1
  • DOI: 10.1042/bj1430115

The Acylation Mechanism of CTX-M β-Lactamase at 0.88 Å Resolution
journal, May 2007

  • Chen, Yu; Bonnet, Richard; Shoichet, Brian K.
  • Journal of the American Chemical Society, Vol. 129, Issue 17
  • DOI: 10.1021/ja0712064

Structural Insights into Substrate Recognition and Product Expulsion in CTX-M Enzymes
journal, July 2010

  • Delmas, Julien; Leyssene, David; Dubois, Damien
  • Journal of Molecular Biology, Vol. 400, Issue 1
  • DOI: 10.1016/j.jmb.2010.04.062

Synthesis, characterization and antibacterial activities of some new ferrocene-containing penems
journal, March 2010

A functional classification scheme for beta-lactamases and its correlation with molecular structure
journal, June 1995

  • Bush, K.; Jacoby, G. A.; Medeiros, A. A.
  • Antimicrobial Agents and Chemotherapy, Vol. 39, Issue 6
  • DOI: 10.1128/AAC.39.6.1211

Streptomycetes excreting dd-carboxypeptidases
journal, July 1990

  • Kurzątkowski, W.; Solecka, J.; Filipek, J.
  • Applied Microbiology and Biotechnology, Vol. 33, Issue 4
  • DOI: 10.1007/BF00176664

Structure, Function, and Inhibition along the Reaction Coordinate of CTX-M β-Lactamases
journal, April 2005

  • Chen, Yu; Shoichet, Brian; Bonnet, Richard
  • Journal of the American Chemical Society, Vol. 127, Issue 15
  • DOI: 10.1021/ja042850a

Organometallic Anticancer Compounds
journal, January 2011

  • Gasser, Gilles; Ott, Ingo; Metzler-Nolte, Nils
  • Journal of Medicinal Chemistry, Vol. 54, Issue 1
  • DOI: 10.1021/jm100020w

Application of ferrocene and its derivatives in cancer research
journal, January 2011

Antibacterial properties and atomic resolution X-ray complex crystal structure of a ruthenocene conjugated β-lactam antibiotic
journal, January 2015

  • Lewandowski, Eric M.; Skiba, Joanna; Torelli, Nicholas J.
  • Chemical Communications, Vol. 51, Issue 28
  • DOI: 10.1039/C5CC00904A

Penicillin Binding Proteins: key players in bacterial cell cycle and drug resistance processes
journal, September 2006

Analysis of the Mechanism of Action of Potent Antibacterial Hetero-tri-organometallic Compounds: A Structurally New Class of Antibiotics
journal, April 2013

  • Wenzel, Michaela; Patra, Malay; Senges, Christoph Helmut Rudi
  • ACS Chemical Biology, Vol. 8, Issue 7
  • DOI: 10.1021/cb4000844

Kinship and Diversification of Bacterial Penicillin-Binding Proteins and β-Lactamases
journal, January 1998

  • Massova, Irina; Mobashery, Shahriar
  • Antimicrobial Agents and Chemotherapy, Vol. 42, Issue 1
  • DOI: 10.1128/AAC.42.1.1
    Sort by:
    [ × clear filter / sort ]

    Works referencing / citing this record:

    Organometallic ciprofloxacin conjugates with dual action: synthesis, characterization, and antimicrobial and cytotoxicity studies
    journal, January 2020

    • Szczupak, Łukasz; Kowalczyk, Aleksandra; Trzybiński, Damian
    • Dalton Transactions, Vol. 49, Issue 5
    • DOI: 10.1039/c9dt03948a

    Synthesis, Structural Characterization and Antimicrobial Activity of Cu(II) and Fe(III) Complexes Incorporating Azo-Azomethine Ligand
    journal, April 2018

    Cymantrenyl-Nucleobases: Synthesis, Anticancer, Antitrypanosomal and Antimicrobial Activity Studies
    journal, December 2017

    Quinoline and ferrocene conjugates: Synthesis, computational study and biological evaluations: Quinoline-ferrocene conjugates
    journal, November 2018

    • Maračić, Silvija; Lapić, Jasmina; Djaković, Senka
    • Applied Organometallic Chemistry, Vol. 33, Issue 1
    • DOI: 10.1002/aoc.4628

    Synthesis, Characterisation and Antimicrobial Studies of some 2,6‐ bis (1,2,3‐Triazol‐4‐yl)Pyridine Ruthenium(II) “Click” Complexes
    journal, March 2019

    • van Hilst, Quinn V. C.; Vasdev, Roan A. S.; Preston, Dan
    • Asian Journal of Organic Chemistry, Vol. 8, Issue 4
    • DOI: 10.1002/ajoc.201900088

    Anticancer and Antibacterial Activity of Transition Metal Complexes
    journal, February 2019

    Antimicrobial activity of organometallic isonicotinyl and pyrazinyl ferrocenyl-derived complexes
    journal, January 2017

    • Stringer, Tameryn; Seldon, Ronnett; Liu, Nicole
    • Dalton Transactions, Vol. 46, Issue 30
    • DOI: 10.1039/c7dt01952a
      Sort by:
      [ × clear filter / sort ]

      Similar Records in DOE PAGES and OSTI.GOV collections: