Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase
Digital Object Identifier (DOI)
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.
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Citation / Publisher Attribution
Organometallics, v. 36, issue 9, p. 1673-1676
Scholar Commons Citation
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" (2017). Molecular Medicine Faculty Publications. 106.