Metallocenyl 7‐ACA Conjugates: Antibacterial Activity Studies and Atomic‐Resolution X‐ray Crystal Structure with CTX‐M β‐Lactamase

Lewandowski, Eric M.; Szczupak, Łukasz; Kowalczyk, Aleksandra; Mendoza, Gracia; Arruebo, Manuel; Jacobs, Lian M. C.; Stączek, Paweł; Chen, Yu; Kowalski, Konrad

doi:10.1002/cbic.202000054

Metallocenyl 7‐ACA Conjugates: Antibacterial Activity Studies and Atomic‐Resolution X‐ray Crystal Structure with CTX‐M β‐Lactamase

Journal Article · Thu Apr 16 00:00:00 EDT 2020 · ChemBioChem: a European journal of chemical biology

DOI:https://doi.org/10.1002/cbic.202000054· OSTI ID:1615058

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Department of Molecular Medicine University of South Florida, >,Morsani College of Medicine 12901 Bruce B. Downs Boulevard Tampa FL 33612 US
Department of Organic Chemistry, Faculty of Chemistry University of Łódź Tamka 12 91-403 Łódź Poland
Department of Microbial Genetics, Faculty of Biology and Environmental Protection University of Łódź Banacha 12/16 90-237 Łódź Poland
Department of Chemical Engineering Aragon Health Research Institute (IIS Aragón) University of Zaragoza Campus Río Ebro-Edificio I+D, c/ Poeta Mariano Esquillor s/n 5018 Zaragoza Spain
Department of Chemical Engineering Aragon Health Research Institute (IIS Aragón) University of Zaragoza Campus Río Ebro-Edificio I+D, c/ Poeta Mariano Esquillor s/n 5018 Zaragoza Spain, Networking Research Center on Bioengineering Biomaterials and Nanomedicine CIBER-BBN 28029 Madrid Spain

Abstract

The conjugation of organometallic groups to current β‐lactam antibiotics is a field of increasing study due to the ability of certain organometallic groups to enhance the antibiotic potency of these drugs. Herein, we report the antibacterial properties of two metallocenyl (ferrocenyl and ruthenocenyl) 7‐aminocephalosporanic acid (7‐ACA) antibiotic conjugates. Continuing a trend we found in our previous studies, the ruthenocenyl conjugate showed greater antibacterial activity than its ferrocenyl counterpart. Compared with the previously published 7‐aminodesacetoxycephalosporanic acid (7‐ADCA) conjugates, the 3‐acetyloxymethyl group significantly improved the compounds’ activity. Furthermore, the Rc‐7‐ACA compound was more active against clinical Staphylococcus aureus isolates than the ampicillin reference. Noticeably, neither of the two new compounds showed an undesirable toxic effect in HeLa and L929 cells at the concentrations at which they displayed strong antibacterial effects. The antibacterial activity of the two metallocenyl 7‐ACA derivatives was further confirmed by scanning electron microscopy (SEM). SEM micrographs showed that bacteria treated with metallocenyl 7‐ACA derivatives feature cell wall damage and morphology changes. Using a CTX‐M‐14 β‐lactamase competition assay based on nitrocefin hydrolysis, we showed that the Rc‐7‐ACA bound more favorably to CTX‐M‐14 than its ferrocenyl counterpart, again confirming the superiority of the ruthenocenyl moiety over the ferrocenyl one in interacting with proteins. We also report a 1.47 Å resolution crystal structure of Rc‐7‐ACA in complex with the CTX‐M‐14 E166A mutant, an enzyme sharing a similar active site configuration with penicillin‐binding proteins, the molecular target of β‐lactam antibiotics. These results strengthen the case for the antibacterial utility of the Rc and Fc groups.

View Accepted Manuscript (Publisher)

Sponsoring Organization:: USDOE

Grant/Contract Number:: W-31109-ENG-38

OSTI ID:: 1615058

Alternate ID(s):: OSTI ID: 1833656

Journal Information:: ChemBioChem: a European journal of chemical biology, Journal Name: ChemBioChem: a European journal of chemical biology Journal Issue: 15 Vol. 21; ISSN 1439-4227

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: France

Language:: English

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