Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo
Activity of capuramycin analogues against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare in vitro and in vivo
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DOI：
10.1093/jac/dkh417
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发表时间：
2004-10-01
影响因子：
5.2
通讯作者：
Hirota, T
中科院分区：
文献类型：
--
作者：
Koga, T;Fukuoka, T;Hirota, T
目的：测定卡普霉素类似物RS-112997、RS-124922和RS-118641对临床分离的结核分枝杆菌、鸟分枝杆菌和胞内分枝杆菌的抑菌活性。方法和结果：mic采用改良的Middlebrook 7H9肉汤微量稀释法测定。RS-118641是最有效的化合物。RS-118641的MIC50/90 （mg/L）结果为：M. tuberculosis, 1/2；耐多药（MDR）结核分枝杆菌，0.5/2；M. avium, 4/8；胞内分枝杆菌为0.06/0.5。在非耐多药和耐多药结核分枝杆菌的MIC分布中，没有观察到任何卡普霉素类似物的统计学差异。为了评价RS-112997和RS-124922对小鼠肺结核肺模型的治疗效果，两种化合物分别以0.1或1mg /只/天的剂量鼻内给药，连续12天。所有治疗组的肺部分枝杆菌负荷均显著低于未治疗组的对照组。进一步实验评价了三种化合物对小鼠胞内支原体感染的治疗效果。所有化合物以0.1 mg/小鼠/天的剂量鼻内给药，持续21天。所有治疗组的肺部分枝杆菌负荷均显著低于未治疗组的对照组。结论：这些结果表明，卡普霉素类似物具有很强的抗细菌潜力，应考虑进一步评估治疗结核分枝杆菌和鸟分枝杆菌。人类细胞内复杂感染。
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.