IRON-REGULATED OUTER-MEMBRANE PROTEINS OF ESCHERICHIA-COLI-K-12 AND MECHANISM OF ACTION OF CATECHOL-SUBSTITUTED CEPHALOSPORINS
IRON-REGULATED OUTER-MEMBRANE PROTEINS OF ESCHERICHIA-COLI-K-12 AND MECHANISM OF ACTION OF CATECHOL-SUBSTITUTED CEPHALOSPORINS
复制标题
DOI：
10.1128/aac.32.12.1879
复制
发表时间：
1988-12-01
影响因子：
4.9
通讯作者：
WHITE, AJ
中科院分区：
文献类型：
--
作者：
CURTIS, NAC;EISENSTADT, RL;WHITE, AJ
选择氨基噻唑肟类头孢菌素在C-3”被儿茶酚部分取代的同源物，用于探索对大肠杆菌K-12的抗菌活性增强的基础，这种活性通常与这种类型的化学修饰有关。有证据表明，这些化合物在大肠杆菌K-12的外膜上存在吨依赖的非法运输，这一过程特别涉及Fiu和Cir铁调节的外膜蛋白。因此，tonB和fiu cir突变体对探针化合物的敏感性都相对降低，而突变体单独缺乏六种铁调节外膜蛋白（fiu, FepA, FecA, FhuA， FhuE和cir）中的任何一种或缺乏这些蛋白的任何两种组合（fiu + cir除外）则没有表现出这种抗性。缺乏所有六种铁调节外膜蛋白的突变体对探针化合物的抗性并不比ficir或tonB菌株强。除后一种基因外，exbB位点和exbC位点的产物也是最大抗菌效力所必需的。抗菌活性依赖于摄取系统成分的表达水平。比较青霉素结合蛋白靶标亲和力和抗菌活性提示大肠杆菌K-12可能在质周积累活性化合物。儿茶酚残基的游离邻羟基是摄取途径识别的主要化学要求，因此具有高抗菌活性。
Selected aminothiazolyl-oxime cephalosporin congeners substituted at C-3'' with a catechol moiety were used to probe the basis of the enhanced antibacterial activity against Escherichia coli K-12 often associated with chemical modifications of this type. Evidence is presented for a tonB-dependent illicit transport of the compounds across the outer membrane of E. coli K-12, the process involving jointly and specifically the Fiu and Cir iron-regulated outer membrane proteins. Thus, both tonB and fiu cir mutants showed a comparably reduced susceptibility to the probe compounds, whereas mutants singularly lacking any one of the six iron-regulated outer membrane proteins (Fiu, FepA, FecA, FhuA, FhuE, and Cir) or lacking any combination of any two of these proteins (except Fiu plus Cir) did not show this resistance. Mutants devoid of all six iron-regulated outer membrane proteins were no more resistant to the probe compounds than fiu cir or tonB strains. In addition to the latter genes, the products of the exbB and possibly the exbC loci were necessary for maximal antibacterial potency. A dependence of antibacterial activity on the level of expression of the uptake system components was noted. Comparison of penicillin-binding protein target affinity with antibacterial activity suggested a possible periplasmic accumulation of active compounds by E. coli K-12. Free vicinal hydroxyl groups of the catechol residue were a primary chemical requirement for recognition by the uptake pathway and thus for high antibacterial activity.