Koga Tetsufumi, Fukuoka Takashi, Doi Norio, Harasaki Tamako, Inoue Harumi, Hotoda Hitoshi, Kakuta Masayo, Muramatsu Yasunori, Yamamura Naotoshi, Hoshi Misa, Hirota Takashi
Biological Research Laboratories, Sankyo Co., Ltd, 2-58 Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan.
J Antimicrob Chemother. 2004 Oct;54(4):755-60. doi: 10.1093/jac/dkh417. Epub 2004 Sep 3.
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.
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.
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.
测试三种抑制磷酸 - N - 乙酰胞壁酰 - 五肽转位酶的卡普霉素类似物RS - 112997、RS - 124922和RS - 118641对结核分枝杆菌、鸟分枝杆菌和胞内分枝杆菌临床分离株的抗分枝杆菌活性。
采用改良的Middlebrook 7H9肉汤通过肉汤微量稀释法测定最低抑菌浓度（MIC）。总体而言，RS - 118641是最有效的化合物。RS - 118641的MIC50/90（mg/L）结果如下：结核分枝杆菌，1/2；耐多药（MDR）结核分枝杆菌，0.5/2；鸟分枝杆菌，4/8；胞内分枝杆菌，0.06/0.5。对于所测试的任何卡普霉素类似物，非MDR和MDR结核分枝杆菌之间在MIC分布上未观察到统计学上的显著差异。为了评估RS - 112997和RS - 124922在小鼠肺结核模型中的治疗效果，两种化合物均以0.1或1 mg/小鼠/天的剂量经鼻给药，持续12天。所有治疗组肺部的分枝杆菌载量均显著低于未治疗的对照组。进行了额外的实验以评估这三种化合物对小鼠胞内分枝杆菌感染的治疗效果。所有化合物均以0.1 mg/小鼠/天的剂量经鼻给药，持续21天。所有治疗组肺部的分枝杆菌载量均显著低于未治疗的对照组。
这些结果表明卡普霉素类似物具有强大的抗分枝杆菌潜力，在治疗人类结核分枝杆菌和鸟 - 胞内分枝杆菌复合感染方面应考虑进一步评估。
