MECHANISM OF TONB-DEPENDENT TRANSPORT OF KP-736, A 1,5-DIHYDROXY-4-PYRIDONE-SUBSTITUTED CEPHALOSPORIN, INTO ESCHERICHIA-COLI K-12 CELLS

The mechanism of transport of KP-736, a novel cephatosporin with a 1,5 -dihydroxy-4-pyridone moiety at the C-7 position, into the Escherichia coil K-12 cell was investigated by determining the susceptibilities o f iron transport mutants to KP-736. The tonB mutant showed a higher de gree of resistance to KP-736, indicating that KP-736 was incorporated into E. coli cells via the tonB-dependent iron transport system. The p roduct of the exbB gene was also necessary for the maximal antibacteri al potency of KP-736. Cir-lacking and Fin-lacking mutants showed a mod erate level of resistance to KP-736. However, mutants lacking any one of the proteins FepA, FecA, FhuA, and FhuE did not show any increased resistance to KP-736. Two types of spontaneous mutants (e.g., KT1004 a nd KT1011) could be isolated from cir and pu mutants by selection for KP-736 resistance and showed the same level of resistance to KP-736 as a tonB mutant. KT1004 showed tonB phenotypes, resistance to phage phi 80, and loss of FecA, whereas KT1011 did not. KT1011 lost the ability to express both Cir and Fiu proteins. These results indicate that the Cir and Fiu outer membrane proteins are involved specifically in the tonB-dependent transport process of KP-736. Against OmpF- and OmpC-def icient transformants producing various groups of beta-lactamases, KP-7 36 was more effective than the other cephalosporins tested.