Oxazolidinones, a new class of synthetic antituberculosis agent in vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis

Abstract

$\text{Dl}\text{-S-n-(3-(4-}\text{acetyl}\text{)-2-}\text{oxo}\text{-5-}\text{oxazolidynyl methyl}\text{)}$ acetamide (DuP-721) is an orally active representative of the oxazolidinone series of antimicrobials. At concentrations ranging from 1.5 to 4 μg/ml, DuP-721 inhibited equally the strains of Mycobacterium tuberculosis susceptible and resistant to conventional antituberculosis drugs. DuP-721 inhibited M. gordonae and M. fortuitum at 3.9 μg/ml, M. kansasii at 1.95, and M. scrofulaceum at 15.6 μg/ml. It was not active against M. avium and M. intracellulare at concentrations of 250 μg/ml. The inhibition of the metabolism of M. tuberculosis as indicated by the liquid scintillation radiometric method was 56% at fourfold the minimum inhibitory concentration (MIC) of DuP-721 that compared well to that of the fourfold MIC concentrations of rifampicin and isoniazid. The in vitro activity of DuP-721 was not affected by reducing the pH from 6.8 to 5.5. In mice infected with M. tuberculosis, the 50% effective dose (ED₅₀) for DuP-721 was 13.2 mg/kg when administered daily beginning 4 hr postinfection for 17 days. The ED₅₀ was 71.8 mg/kg when DuP-721 was administered only on days 11 and 12 postinfection. A 100% survival rate was obtained at 50 and 160 mg/kg when DuP-721 was administered daily for 17 days, and only on days 11 and 12 after the infection, respectively. The increase in the survival time by DuP-721 at 100 mg/kg (eightfold the ED₅₀ dose) when administered daily for 17 days beginning 4 hr after infection was inferior to that by eightfold the ED₅₀ dose of rifampicin and isoniazid administered on days 11 and 12 postinfection. These results indicate that DuP-721 is protective against M. tuberculosis infection in mice, and further investigations with other compounds belonging to the oxazolidinone series are warranted.