Dual-action antibacterials: A concept newly realized for antibacterial chemotherapy

Abstract

Ro 23-9424 represents the culmination of an idea put forth by O'Callaghan et al 4 in 1976. They proposed that a cephalosporin could act as a carrier for a second antibacterial with the total molecule functioning as a single antibacterial until separated by opening of the ß-lactam ring by a ß-lactamase or, as we now know, the target penicillin-sensitive enzymes. It is important to note that in spite of the ester linkage, hydrolysis of Ro 23-9424 in animals to the components is minimal and the elimination kinetics are those of a single molecule with a pharmacokinetic profile of the cephalosporin component. The results of our preliminary toxicology studies in rats and dogs also suggest that this compound will have a safety profile similar to that of the cephalosporin component. This would allow parenteral administration of the quinolone component, fleroxacin, at a much higher dosage than is possible with the free quinolone. Ro 23-9424 represents the first of a new class of antibacterials. The major constraint in designing new compounds within this class will only be the ingenuity of the pharmaceutical chemist.