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

Abstract

Oxidation of beta-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 (k(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 beta-lactams (k(app) for pH 7 = 110-770 M-1 s(-1)). The pH-dependent k(app) could be well explained by considering species-specific reactions between ferrate(VI) and the beta-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 beta-lactams was transformed to stereoisomeric (R)- and (S)-sulfoxides and then to a sulfone. Quantitative microbiological assay of ferrate(VI)-treated beta-lactam solutions indicated that transformation products resulting from the oxidation of cephalexin exhibited diminished, but non-negligible residual activity (i.e., similar to 24% as potent as the parent compound). For the other beta-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 beta-lactams, although alternative approaches may be necessary to achieve complete elimination of cephalosporin activities.