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

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.