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

作者：Lewandowski Eric M; Szczupak Lukasz; Wong Stephanie; Skiba Joanna; Gugpie Adam; Solecka Jolanta; Vrcek Valerije; Kowalski Konrad^*; Chen Yu^*

来源：Organometallics, 2017, 36(9): 1673-1676.

DOI：10.1021/acs.organomet.6b00888

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 aryl-enzyme complex of a ruthenocenyl compound with CTX-M beta-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 beta-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.

• 出版日期2017-5-8