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

Abstract

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 DD-carboxypeptidase 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

Cite this paper

@article{Lewandowski2017AntibacterialPO, title={Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase.}, author={Eric M Lewandowski and Łukasz Szczupak and Stephanie K. Wong and Joanna Skiba and Adam Guśpiel and Jolanta Solecka and Valerije Vr{\vc}ek and Konrad Kowalski and Yu Chen}, journal={Organometallics}, year={2017}, volume={36 9}, pages={1673-1676} }