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

Diagn Microbiol Infect Dis. 1991 Nov-Dec;14(6):465-71. doi: 10.1016/0732-8893(91)90002-w.

Abstract

DL-S-n-(3-(4-acetyl)-2-oxo-5-oxazolidynyl methyl) acetamide (DuP-721) is an orally active representative of the oxazolidinone series of antimicrobials. At concentrations ranging from 1.5 to 4 micrograms/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 micrograms/ml, M. kansasii at 1.95, and M. scrofulaceum at 15.6 micrograms/ml. It was not active against M. avium and M. intracellulare at concentrations of 250 micrograms/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.(ABSTRACT TRUNCATED AT 250 WORDS)

MeSH terms

  • Animals
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / therapeutic use
  • Dose-Response Relationship, Drug
  • Drug Resistance, Microbial
  • Female
  • Hydrogen-Ion Concentration
  • Mice
  • Mycobacterium avium / drug effects
  • Mycobacterium avium Complex / drug effects
  • Mycobacterium scrofulaceum / drug effects
  • Mycobacterium tuberculosis / drug effects*
  • Nontuberculous Mycobacteria / drug effects*
  • Oxazoles / pharmacology*
  • Oxazoles / therapeutic use
  • Oxazolidinones
  • Tuberculosis / drug therapy*

Substances

  • Antitubercular Agents
  • Oxazoles
  • Oxazolidinones
  • 4-acetylphenyloxooxazolidinylmethylacetamide