Mode of action of the dual-action cephalosporin Ro 23-9424

Abstract

Ro 23-9424 is a broad-spectrum antibacterial agent composed of a cephalosporin and a quinolone moiety. Its biological properties were compared with those of its two components and structurally related cephalosporins and quinolones. Like ceftriaxone and cefotaxime but unlike its decomposition product, desacetyl cefotaxime, Ro 23-9424 bound at c2 ,ug/ml to the essential penicillin-binding proteins lb and 3 of Escherichia coli and 1, 2, and 3 of Staphylococcus aureus. In E. coli, Keith, 28th ICAAC, abstr. no. 448, 1988

Discovery and development of new antibiotics: the problem of antibiotic resistance

“…In theory, cephalosporin-susceptible cells would be inactivated by the cephalosporin moiety; if a cephalosporinase were present, it would liberate the quinolone moiety, which could penetrate the cytoplasm and reach its target. While the details of this lactamase activation have not been proven, it is clear that the compound both binds to penicillin-binding proteins and inhibits replicative DNA synthesis (16). Perhaps a quinolone derivative could be designed to contain a moiety which inhibits a second cytoplasmic target in addition to DNA gyrase.…”

“…One approach is to design a dual-action molecule that has two different targets, such as the Roche quinolone cephalosporin Ro23-9424 (16). In theory, cephalosporin-susceptible cells would be inactivated by the cephalosporin moiety; if a cephalosporinase were present, it would liberate the quinolone moiety, which could penetrate the cytoplasm and reach its target.…”

Low-level resistance to the cephalosporin 3'-quinolone ester Ro 23-9424 in Escherichia coli

“…Its mode of action in Escherichia coli involves initial binding to penicillin-binding protein (PBP) 3, resulting in inhibition of septation. The quinolone moiety is subsequently released, which then inhibits DNA gyrase activity (4,6,8).…”

“…Its mode of action in Escherichia coli involves initial binding to penicillin-binding protein (PBP) 3, resulting in inhibition of septation. The quinolone moiety is subsequently released, which then inhibits DNA gyrase activity (4,6,8).As part of the biological characterization of Ro 23-9424, E. coli mutants resistant to it were isolated and the mechanism of their resistance was examined.Bacterial strains are listed in Table 1. Organisms were routinely grown in antibiotic medium 3 or nutrient broth (Difco Laboratories, Detroit, Mich.) at 37ЊC.…”

In vitro activity of Ro 23-9424, a dual-action cephalosporin, compared with activities of other antibiotics

“…Ro 23-9424 is a novel compound in which the microbiologically active cefotaxime metabolite desacetyl-cefotaxime is linked by an ester bond at the C-3 position to the carboxy group of the quinolone fleroxacin. Initial studies showed that Ro 23-9424 combines the antibacterial spectrum and potency of both desacetyl-cefotaxime and fleroxacin (2,4). This study was designed to determine the activity of this compound against a number of different species of bacteria and to compare its activity with those of cefotaxime, desacetylcefotaxime, fleroxacin, and two other fluoroquinolone compounds.…”