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:
-
- Univ. of South Florida, Tampa, FL (United States). Morsani College of Medicine
- Univ. of Łódź, Tamka (Poland)
- National Inst. of Public Health - National Inst. of Hygiene (NIPH-NIH), Warsaw (Poland)
- 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}
}
Web of Science
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