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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]
  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:
Journal Article: 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.
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
Lewandowski, Eric M., Szczupak, Łukasz, Wong, Stephanie, Skiba, Joanna, Guśpiel, Adam, Solecka, Jolanta, Vrček, Valerije, Kowalski, Konrad, and Chen, Yu. 2017. "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.
@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},
url = {https://www.osti.gov/biblio/1463718}, journal = {Organometallics},
issn = {0276-7333},
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}
}

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


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


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