Configuration of the methoxyimino group and penetration ability of cefotaxime and its structural analogues.

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Abstract
Cefotaxime [CTX], which passesses a methoxyimino group in the syn-configuration in the acylamino side chain, was compared for affinity to PBP [penicillin-binding proteins] and penetration ability with its isomer possessing the same group in the anti-configuration and the corresponding demethoxyimino derivative. The anti-isomer, although resistant to .beta.-lactamase, was devoid of antibacterial activity (minimum inhibitory concentration for Escherichia coli > 500 .mu.g/ml). The affinities of CTX and its analogs for the PBP of several strains of E. coli were determined in vivo and in vitro by competition experiments using intact cells and bacterial envelopes, respectively. Only minor differences in the affinity for the target PBP were detected in vitro. In vivo studies proved that the 50% saturating concentrations for the PBP were > 100-fold higher for the anti-isomer than for CTX. Evidently, a very simple structural modification of the CTX molecule greatly decreases the penetration ability of the antibiotic through the outer cell layers, thus dramatically affecting its antibacterial properties.