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

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.

Synthesis and antimycobacterial activity of capuramycin analogues. Part 1: substitution of the azepan-2-one moiety of capuramycin.

Capuramycin analogues with a variety of substituents in place of the azepan-2-one moiety were synthesized from A-500359E and were tested for their translocase I inhibitory activity and in vitro antimycobacterial activity. Phenyl-type moieties were found to be effective substituents for capuramycin analogues.

Synthesis and evaluation of novel pyrrolidinyl sordaricin derivatives as antifungal agents.

N-Benzyl pyrrolidinyl sordaricin derivatives have been synthesized from cis-4-hydroxy-D-proline in a stereocontrolled manner. These compounds maintained moderate antifungal activity against several pathogenic fungal strains. Their MIC values against Candida albicans were in the range of 0.25-2 microg/mL.

Synthesis and evaluation of N-substituted 1,4-oxazepanyl Sordaricins as selective fungal EF-2 inhibitors.

Sordaricin analogues possessing 6-methoxy-7-methyl-1,4-oxazepane moiety instead of the sugar part were synthesized and evaluated. It was found that N-substituents on the oxazepane ring had influence on biological activity. In particular, N-(2-methylpropenyl) derivative 12p exhibited potent in vitro antifungal activity. Furthermore, 12p maintained significant activity (MIC 0.25 microg/mL) against Candida albicans SANK51486 even in the presence of 20% horse serum.

Synthesis of Sordaricin analogues as potent antifungal agents against Candida albicans.

Sordaricin derivatives possessing a cyclohexane ring appendage attached via an ether, thioether, amine, oxime, ester or amide linkage were synthesized and their antifungal activity was evaluated in vitro. Compounds containing a thioether bond or an oxime bond as a linkage exhibited potent MICs (< or = 0.125 microg/mL) against four Candida albicans strains including azole-low-susceptible strains. They were also active (MIC < or = 0.125 microg/mL) against Candida glabrata. Their in vivo efficacy was confirmed in a murine intravenous infection model with Candida albicans.

In vitro and in vivo activities of CS-758 (R-120758), a new triazole antifungal agent.

The activity of CS-758 (R-120758), a new triazole antifungal agent, was evaluated and compared with those of fluconazole, itraconazole, and amphotericin B in vitro and with those of fluconazole and itraconazole in vivo. CS-758 exhibited potent in vitro activity against clinically important fungi. The activity of CS-758 against Candida spp. was superior to that of fluconazole and comparable or superior to those of itraconazole and amphotericin B. CS-758 retained potent activity against Candida albicans strains with low levels of susceptibility to fluconazole (fluconazole MIC, 4 to 32 microg/ml). Against Aspergillus spp. and Cryptococcus neoformans, the activity of CS-758 was at least fourfold superior to those of the other drugs tested. CS-758 also exhibited potent in vivo activity against murine systemic infections caused by C. albicans, C. neoformans, Aspergillus fumigatus, and Aspergillus flavus. The 50% effective doses against these infections were 0.41 to 5.0 mg/kg of body weight. These results suggest that CS-758 may be useful in the treatment of candidiasis, cryptococcosis, and aspergillosis.