Electron Transfer Mechanism for β-lactam Antibiotic Action via Side-Chain Imine

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16 p.

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Bioorganic Chemistry

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Evidence has been previously presented for an electron transfer (ET) component associated with the mechanism of action of β-lactam antibiotics, in addition to enzyme inactivation. For the fused-ring types, apparently the ET entity is a conjugated iminium group formed as a result of ring-opening. We now report on the feasibility of ET associated with several monocyclic and cephalosporin β-lactams that contain conjugated imine in the acyl side chain. The side chain assumes increased importance for the monobactams and nocardicins since ring scission does not generate iminium. The monocyclic agents generally reduced in the favorable range of −0.5 to −0.6 V at pH 4.1. The cephalosporin drugs potentially contain two electroactive sites, iminiums from ring-opening and from generation in the side chain. Electroreduction involving the side-chain oxime occurred at about −0.4 to −0.7 V (pH 4.1). Model compounds are used to provide additional mechanistic insight. There are various sources of hydrogen ions needed for iminium formation at the active site. Comparisons are made between reduction potential and antibiotic activity. The mode of bactericidal action is discussed with focus on ET by iminium.


Bioorganic Chemistry, Vol. 16, No. 2 (June 1988): 149-164. DOI.