Ferrate(VI) Oxidation of β‑Lactam Antibiotics: Reaction Kinetics, Antibacterial Activity Changes, and Transformation Products

Oxidation of β-lactam antibiotics by aqueous ferrate­(VI) was investigated to determine reaction kinetics, reaction sites, antibacterial activity changes, and transformation products. Apparent second-order rate constants (<i>k</i>_app) were determined in the pH range 6.0–9.5 for the reaction of ferrate­(VI) with penicillins (amoxicillin, ampicillin, cloxacillin, and penicillin G), a cephalosporin (cephalexin), and several model compounds. Ferrate­(VI) shows an appreciable reactivity toward the selected β-lactams (<i>k</i>_app for pH 7 = 110–770 M^–1 s^–1). The pH-dependent <i>k</i>_app could be well explained by considering species-specific reactions between ferrate­(VI) and the β-lactams (with reactions occurring at thioether, amine, and/or phenol groups). On the basis of the kinetic results, the thioether is the main reaction site for cloxacillin and penicillin G. In addition to the thioether, the amine is a reaction site for ampicillin and cephalexin, and amine and phenol are reaction sites for amoxicillin. HPLC/MS analysis showed that the thioether of β-lactams was transformed to stereoisomeric (<i>R</i>)- and (<i>S</i>)-sulfoxides and then to a sulfone. Quantitative microbiological assay of ferrate­(VI)-treated β-lactam solutions indicated that transformation products resulting from the oxidation of cephalexin exhibited diminished, but non-negligible residual activity (i.e., ∼24% as potent as the parent compound). For the other β-lactams, the transformation products showed much lower (<5%) antibacterial potencies compared to the parent compounds. Overall, ferrate­(VI) oxidation appears to be effective as a means of lowering the antibacterial activities of β-lactams, although alternative approaches may be necessary to achieve complete elimination of cephalosporin activities