title: Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo.
abstract: OBJECTIVE
  The antimycobacterial activities of RS-112997, RS-124922 and RS-118641, three capuramycin analogues that inhibit phospho-N-acetylmuramyl-pentapeptide translocase, were tested against clinical isolates of Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare.
  
  
  RESULTS
  MICs were determined by the broth microdilution method using a modified Middlebrook 7H9 broth. RS-118641 was the most potent compound overall. The MIC50/90 (mg/L) results for RS-118641 were: M. tuberculosis, 1/2; multidrug-resistant (MDR) M. tuberculosis, 0.5/2; M. avium, 4/8; and M. intracellulare, 0.06/0.5. No statistically significant differences in MIC distributions were observed between non-MDR and MDR M. tuberculosis for any of the capuramycin analogues tested. In order to evaluate the therapeutic efficacy of RS-112997 and RS-124922 in a murine lung model of tuberculosis, both compounds were administered intranasally at 0.1 or 1 mg/mouse/day for 12 days. The mycobacterial load in the lungs was significantly lower in all treatment groups than in the untreated controls. Additional experiments were performed to evaluate the therapeutic efficacy of the three compounds against the M. intracellulare infection in mice. All compounds were administered intranasally at 0.1 mg/mouse/day for 21 days. The mycobacterial load in the lungs was significantly lower in all treatment groups than in the untreated controls.
  
  
  CONCLUSIONS
  These results suggest that capuramycin analogues exhibit strong antimycobacterial potential and should be considered for further evaluation in the treatment of M. tuberculosis and M. avium-M. intracellulare complex infections in humans.
authors.affiliation: Biological Research Laboratories, Sankyo Co., Ltd, 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan. tekoga@sankyo.co.jp
authors.forename: Tetsufumi
authors.initials: T
authors.lastname: Koga
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukuoka
authors.forename: Norio
authors.initials: N
authors.lastname: Doi
authors.forename: Tamako
authors.initials: T
authors.lastname: Harasaki
authors.forename: Harumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hotoda
authors.forename: Masayo
authors.initials: M
authors.lastname: Kakuta
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Muramatsu
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Yamamura
authors.forename: Misa
authors.initials: M
authors.lastname: Hoshi
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirota
mesh_terms: D000281:Administration, Intranasal; D000617:Aminoglycosides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects*; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D015270:Mycobacterium avium-intracellulare Infection / Q000188:drug therapy; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
chemical_list: D000617:Aminoglycosides; D000995:Antitubercular Agents; C049983:capuramycin