RESUMEN
Capuramycin (1) and its analogs are strong translocase I (MurX/MraY) inhibitors. In our structure-activity relationship studies of capuramycin analogs against Mycobacterium tuberculosis (Mtb), we observed for the first time that a capuramycin analog, UT-01320 (3) killed nonreplicating (dormant) Mtb at low concentrations under low oxygen conditions, whereas selective MurX inhibitors killed only replicating Mtb under aerobic conditions. Interestingly, 3 did not exhibit MurX enzyme inhibitory activity even at high concentrations, however, 3 inhibited bacterial RNA polymerases with the IC50 values of 100-150 nM range. A new RNA polymerase inhibitor 3 displayed strong synergistic effects with a MurX inhibitor SQ 641 (2), a promising preclinical tuberculosis drug.
Asunto(s)
Aminoglicósidos/farmacología , Antituberculosos/farmacología , Caprolactama/análogos & derivados , Inhibidores Enzimáticos/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Uridina/análogos & derivados , Aminoglicósidos/administración & dosificación , Aminoglicósidos/química , Antituberculosos/administración & dosificación , Antituberculosos/química , Proteínas Bacterianas/antagonistas & inhibidores , Caprolactama/administración & dosificación , Caprolactama/farmacología , ARN Polimerasas Dirigidas por ADN/antagonistas & inhibidores , Sinergismo Farmacológico , Inhibidores Enzimáticos/administración & dosificación , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana , Oxígeno/metabolismo , Relación Estructura-Actividad , Transferasas/antagonistas & inhibidores , Transferasas (Grupos de Otros Fosfatos Sustitutos) , Uridina/administración & dosificación , Uridina/farmacologíaRESUMEN
Aurachin RE (1) is a strong antibiotic that was recently found to possess 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) and bacterial electron transport inhibitory activities. Aurachin RE is the only molecule in a series of aurachin natural products that has the chiral center in the alkyl side chain at C9'-position. To identify selective MenA inhibitors against Mycobacterium tuberculosis , a series of chiral molecules were designed based on the structures of previously identified MenA inhibitors and 1. The synthesized molecules were evaluated in in vitro assays, including MenA enzyme and bacterial growth inhibitory assays. We could identify novel MenA inhibitors that showed significant increase in potency of killing nonreplicating M. tuberculosis in the low oxygen recovery assay (LORA) without inhibiting other Gram-positive bacterial growth even at high concentrations. The MenA inhibitors reported here are useful new pharmacophores for the development of selective antimycobacterial agents with strong activity against nonreplicating M. tuberculosis.
