title: Chemotherapeutic activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium tuberculosis in C57BL/6 mice.
abstract: OBJECTIVE
  To investigate the chemotherapeutic activity of benzoxazinorifamycin, KRM-1648, in comparison with rifabutin (RFB) and rifampin (RIF) against experimental tuberculosis.
  
  
  METHODS
  C57BL/6 mice were infected with 10(5)-10(6) colony forming units (CFU) of either drug-susceptible virulent Mycobacterium tuberculosis (H37Rv) or multi-drug resistant (MDR) M. tuberculosis strain (2230) and were treated from the next day (early treatment) or after 2 weeks following infection (established infection) with 20 mg/kg dose of each drug or none (untreated control). The efficacy of chemotherapy was assessed based on prevention of mortality and on CFU levels in the lungs and spleens.
  
  
  RESULTS
  All three drugs prevented mortality for up to 28 weeks of observation, while all the untreated control mice died by 4 weeks. Analysis of CFUs revealed superior therapeutic activity of both KRM-1648 and RFB as compared to RIF against the drug-susceptible strain of M. tuberculosis under the early treatment protocol. Twelve weeks' treatment with KRM-1648 or RFB caused complete sterilization of the lungs. However, residual organisms started appearing in the spleens 6 weeks after cessation of treatment with RFB and 16 weeks after KRM-1648 treatment. In mice infected with a MDR strain of M. tuberculosis, which was susceptible in vitro to KRM-1648, the drug did not appear to have any activity. Since the MDR organisms did not multiply in vivo, and did not cause any mortality up to 28 weeks in the RIF-treated control mice, a state of semi-dormancy of the organisms which might prevail in vivo could be responsible for refractoriness to treatment with KRM-1648.
  
  
  CONCLUSIONS
  KRM-1648 showed an excellent chemotherapeutic activity, as compared to RFB and RIF, against drug-susceptible tuberculosis. However, all three analogues were ineffective against infection with multi-drug resistant strain of M. tuberculosis.
authors: Dept of Medicine, University of Illinois at Chicago 60612, USA.
authors: M V
authors: MV
authors: Reddy
authors: J
authors: J
authors: Luna-Herrera
authors: D
authors: D
authors: Daneluzzi
authors: P R
authors: PR
authors: Gangadharam
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D005260:Female; D008168:Lung / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D017828:Rifabutin / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D012294:Rifamycins / Q000627:therapeutic use*; D013154:Spleen / Q000382:microbiology; D014376:Tuberculosis / Q000188:drug therapy* / Q000401:mortality; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy
chemical_list: D000904:Antibiotics, Antitubercular; D012294:Rifamycins; C068980:KRM 1648; D017828:Rifabutin; D012293:Rifampin