RESUMEN
A cell-based phenotypic screen for inhibitors of biofilm formation in mycobacteria identified the small molecule TCA1, which has bactericidal activity against both drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb) and sterilizes Mtb in vitro combined with rifampicin or isoniazid. In addition, TCA1 has bactericidal activity against nonreplicating Mtb in vitro and is efficacious in acute and chronic Mtb infection mouse models both alone and combined with rifampicin or isoniazid. Transcriptional analysis revealed that TCA1 down-regulates genes known to be involved in Mtb persistence. Genetic and affinity-based methods identified decaprenyl-phosphoryl-ß-D-ribofuranose oxidoreductase DprE1 and MoeW, enzymes involved in cell wall and molybdenum cofactor biosynthesis, respectively, as targets responsible for the activity of TCA1. These in vitro and in vivo results indicate that this compound functions by a unique mechanism and suggest that TCA1 may lead to the development of a class of antituberculosis agents.
Asunto(s)
Antituberculosos/farmacología , Benzotiazoles/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tiofenos/farmacología , Tuberculosis Pulmonar/tratamiento farmacológico , Oxidorreductasas de Alcohol , Secuencia de Aminoácidos , Animales , Antituberculosos/administración & dosificación , Antituberculosos/química , Proteínas Bacterianas/antagonistas & inhibidores , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Benzotiazoles/administración & dosificación , Benzotiazoles/química , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Carbohidrato Epimerasas/antagonistas & inhibidores , Carbohidrato Epimerasas/química , Carbohidrato Epimerasas/genética , Farmacorresistencia Bacteriana , Femenino , Genes Bacterianos , Ensayos Analíticos de Alto Rendimiento , Isoniazida/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana , Datos de Secuencia Molecular , Mycobacterium tuberculosis/enzimología , Mycobacterium tuberculosis/genética , Oxidorreductasas/antagonistas & inhibidores , Oxidorreductasas/química , Oxidorreductasas/genética , Rifampin/administración & dosificación , Tiofenos/administración & dosificación , Tiofenos/química , Tuberculosis Pulmonar/microbiologíaRESUMEN
In the recently concluded REMox-TB trial, two 4-month moxifloxacin-containing regimens did not meet the criteria for noninferiority compared to the current 6-month first-line regimen to treat tuberculosis (TB). Despite the disappointing result, this phase 3 clinical trial provides a rare opportunity to gauge the predictive accuracy of the nonclinical models used to support regimen development. In parallel with the REMox-TB trial, we compared the efficacy of the same three regimens against chronic TB infection in the commonly used BALB/c mouse strain and in C3HeB/FeJ mice, which have attracted recent interest as a nonclinical efficacy model because they develop caseous lung lesions which may better resemble human TB. In long-term treatment experiments at two institutions, using low-dose aerosol infection models with 6- to 8-week incubation periods in both mouse strains, control mice received rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE), and test mice received the same regimen with moxifloxacin replacing isoniazid (RMZE) or ethambutol (RHZM). Outcome measures were lung CFU counts during treatment and relapse after various durations of treatment. At both institutions and in both mouse strains, RMZE and RHZM reduced by approximately 1 month and 0 to 1 month, respectively, the treatment duration needed to produce the same relapse rate as RHZE. These results demonstrating generally similar treatment-shortening effects of the moxifloxacin-containing regimens in each mouse strain, with effect sizes consistent with the REMox-TB trial results, reinforce the predictive value of murine models for TB regimen development.