Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis.
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)
Ashtekar
D R
DR
Hindustan CIBA-GEIGY Infectious Diseases Programme, Pharma Research Center, Goregaon Bombay, India.
Costa-Periera
R
R
Shrinivasan
T
T
Iyyer
R
R
Vishvanathan
N
N
Rittel
W
W
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial; D005260:Female; D006863:Hydrogen-Ion Concentration; D051379:Mice; D009162:Mycobacterium avium / Q000187:drug effects; D015269:Mycobacterium avium Complex / Q000187:drug effects; D015359:Mycobacterium scrofulaceum / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009170:Nontuberculous Mycobacteria / Q000187:drug effects*; D010080:Oxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D023303:Oxazolidinones; D014376:Tuberculosis / Q000188:drug therapy*
D000995:Antitubercular Agents; D010080:Oxazoles; D023303:Oxazolidinones; C054755:4-acetylphenyloxooxazolidinylmethylacetamide