RESUMEN
The historical view of ß-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis (Mtb) in the presence of a ß-lactamase inhibitor. However, most antimycobacterial ß-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 ß-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3' that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a ß-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A ß-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent ß-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states.
Asunto(s)
Antituberculosos/farmacología , Cefalosporinas/farmacología , Replicación del ADN , Mycobacterium tuberculosis/efectos de los fármacos , Piridinas/farmacología , Tionas/farmacología , Administración Oral , Animales , Antituberculosos/administración & dosificación , Callithrix , Cefalosporinas/administración & dosificación , Descubrimiento de Drogas , Femenino , Células Hep G2 , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Mycobacterium tuberculosis/fisiología , Piridinas/administración & dosificación , Tionas/administración & dosificaciónRESUMEN
A systematic study of the stability of a set of cephalosporins in mouse plasma reveals that cephalosporins lacking an acidic moiety at C-2 may be vulnerable to ß-lactam cleavage in mouse plasma.