Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo.

Abstract

OBJECTIVES:

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.

METHODS AND 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: Tetsufumi Koga, Takashi Fukuoka, Norio Doi, Tamako Harasaki, Harumi Inoue, Hitoshi Hotoda, Masayo Kakuta, Yasunori Muramatsu, Naotoshi Yamamura, Misa Hoshi, Takashi Hirota
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 54 Issue 4 Pg. 755-60 (Oct 2004) ISSN: 0305-7453 [Print] England
• PMID: 15347635 (Publication Type: Journal Article)

Chemical References

• Aminoglycosides
• Antitubercular Agents
• capuramycin

Topics

• Administration, Intranasal
• Aminoglycosides (administration & dosage, pharmacology, therapeutic use)
• Animals
• Antitubercular Agents (administration & dosage, pharmacology, therapeutic use)
• Disease Models, Animal
• Female
• Mice
• Mice, Inbred BALB C
• Microbial Sensitivity Tests
• Mycobacterium avium (drug effects)
• Mycobacterium avium Complex (drug effects)
• Mycobacterium avium-intracellulare Infection (drug therapy)
• Mycobacterium tuberculosis (drug effects)
• Tuberculosis, Pulmonary (drug therapy)