OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.
OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.
复制标题
OPC-67683，一种硝基二氢 - 米达佐尔衍生物，在体外和小鼠中针对结核病有前途的作用。
DOI：
10.1371/journal.pmed.0030466
复制
发表时间：
2006-11
期刊：
影响因子：
15.8
通讯作者：
Komatsu, Makoto
中科院分区：
文献类型：
--
作者：
Matsumoto, Makoto;Hashizume, Hiroyuki;Tomishige, Tatsuo;Kawasaki, Masanori;Tsubouchi, Hidetsugu;Sasaki, Hirofumi;Shimokawa, Yoshihiko;Komatsu, Makoto
结核病 (TB) 仍然是全世界死亡的主要原因。世界上几乎有三分之一的人口感染了结核杆菌，每年约有 800 万人患上活动性结核病，200 万人因此死亡。如今的结核病治疗可以追溯到 20 世纪 70 年代，治疗时间长且繁重，需要至少 6 个月的多种药物化疗。耐多药结核病（MDR-TB）的出现以及该感染与艾滋病毒/艾滋病的致命协同作用使情况进一步复杂化。全球卫生和慈善组织现在正在呼吁新的药物干预措施，以解决结核病治疗中这些未满足的需求。我们在此报告 OPC-67683，这是一种硝基二氢咪唑并恶唑衍生物，经过筛选可帮助解决结核病治疗中未满足的需求。该化合物是一种分枝菌酸生物合成抑制剂，不具有致突变性，并且对结核病（包括耐多药结核病）具有高效活性，体外最低抑制浓度 (MIC) 范围极低，为 0.006–0.024 μg/ml，体内低剂量具有高效治疗活性。此外，OPC-67683 对细胞内结核分枝杆菌的抗生素后效应结果表明，在脉冲暴露 4 小时后，该药物对细胞内结核分枝杆菌 H37Rv 也具有高度且剂量依赖性的活性，并且这种活性在浓度为 0.1 μg/ml 时与一线药物利福平 (RFP) 在 1 小时的活性相似。 浓度为3微克/毫升。与由 RFP、异烟肼 (INH)、乙胺丁醇 (EB) 和 PZA 组成的标准方案相比，OPC-67683 与 RFP 和吡嗪酰胺 (PZA) 的组合可显着更快地根除肺部活结核杆菌（至少 2 个月）。此外，OPC-67683 不受肝微粒体酶的影响，也不会影响肝微粒体酶的活性，这表明 OPC-67683 可以与诱导细胞色素 P450 酶或被细胞色素 P450 酶代谢的药物（包括抗逆转录病毒药物）联合使用。我们的结论是，基于这些特性，OPC-67683 有潜力用作结核病药物，以帮助解决结核病治疗中未满足的需求。硝基-二氢-咪唑并恶唑衍生物被证明具有抗结核病的潜力。世界上三分之一的人口感染了结核分枝杆菌，这种细菌会导致结核病 (TB)。大多数感染者都是健康的——细菌可以潜伏多年，隐藏在体内的细胞内。然而，每年有 800 万人患上活动性结核病（一种通常影响肺部的慢性疾病），并导致 200 万人死亡。在 20 世纪下半叶的大部分时间里，由于 20 世纪 40 年代以来开发出的强效抗生素，结核病呈下降趋势。结核病的标准治疗方法是 4 种抗生素，必须每周服用几次，持续至少六个月才能清除任何潜在的结核分枝杆菌，这种方法于 20 世纪 70 年代末推出，挽救了许多生命。然而，最近，艾滋病毒/艾滋病的流行（免疫系统受损的人非常容易感染结核病）以及多重耐药（MDR）细菌的出现，使根除结核病的努力受挫。结核病的治疗过程漫长且令人不快，患有耐多药结核病的患者必须使用效果较差、价格更高且毒性更大的二线药物进行治疗。此外，对于同时感染艾滋病毒和结核病的人，一些抗逆转录病毒药物和抗结核药物不能同时使用。许多药物会被肝脏中的酶激活或清除，因此这两类药物的组合有时会改变肝功能，从而导致临床问题。因此，迫切需要新的、有效的抗结核药物，以不同于现有药物的方式攻击结核分枝杆菌。理想情况下，此类药物应能有效对抗耐多药结核分枝杆菌，以低剂量快速起效，有效对抗潜伏细菌，并且对肝脏的影响最小，以便可用于同时感染艾滋病毒的患者。在这项研究中，研究人员研究了一种名为 OPC-67683 的化学物质。研究人员发现了一种抑制分枝菌酸（结核分枝杆菌细胞壁的重要成分）产生的化合物，并测试了其杀死该生物体的能力。然后，他们详细测试了其抑制抗生素敏感和耐多药结核分枝杆菌培养皿中细菌生长的能力以及患者分离株的能力。 OPC-67683 能够以低于标准结核病治疗中使用的四种抗生素的浓度抑制所有这些细菌的生长。它还能杀死隐藏在人体细胞内的细菌，效果与这些药物一样好，甚至更好。接下来，研究人员用 OPC-67683 治疗了感染结核分枝杆菌的小鼠。他们发现，与标准药物相比，它以较低的浓度减少了正常小鼠和免疫功能低下小鼠肺部的细菌数量。此外，当与两种标准药物结合使用时，它可以将标准药物方案清除肺部细菌所需的时间缩短两个月。最后，研究人员表明 OPC-67683 对代谢抗逆转录病毒药物的肝酶没有影响，相反，OPC-67683 的活性不受肝酶的影响。因此，这种药物不太可能引起临床问题或对正在接受抗逆转录病毒药物的艾滋病毒患者失去疗效。实验室和动物实验的这些结果表明 OPC-67683 可能满足新型抗结核药物的标准。 OPC-67683 对耐多药结核病具有活性。它对细胞内结核病也有活性，作者推测这可能与潜伏性结核病的有效治疗有积极的联系，并且当与现有的抗结核药物结合使用时，它在动物身上起效很快。重要的是，它还以独特的方式抑制结核分枝杆菌，并且似乎不会对肝脏产生任何可能阻止其与抗逆转录病毒药物联合使用的重大影响。所有这些临床前特征现在都需要在人体中进行检查——许多药物在临床前研究中表现良好，但在患者身上却失败了。鉴于结核病的激增，这些临床研究需要加快，研究人员写道，OPC-67683需要与常规药物和其他新药联合进行测试，以便尽快找到治疗结核病的最佳新药方案。请通过此摘要的在线版本访问这些网站：http://dx.doi.org/10.1371/journal.pmed.0030466。 美国国家过敏和传染病研究所有关结核病的患者情况说明书 美国疾病控制和预防中心有关结核病的信息 MedlinePlus 有关结核病的百科全书条目 NHS Direct 在线结核病患者信息 来自英国国家卫生服务局 世界卫生组织有关全球消除结核病的信息 全球结核病药物开发联盟 有关为何需要新结核病药物的信息
Tuberculosis (TB) is still a leading cause of death worldwide. Almost a third of the world's population is infected with TB bacilli, and each year approximately 8 million people develop active TB and 2 million die as a result. Today's TB treatment, which dates back to the 1970s, is long and burdensome, requiring at least 6 mo of multidrug chemotherapy. The situation is further compounded by the emergence of multidrug-resistant TB (MDR-TB) and by the infection's lethal synergy with HIV/AIDS. Global health and philanthropic organizations are now pleading for new drug interventions that can address these unmet needs in TB treatment. Here we report OPC-67683, a nitro-dihydro-imidazooxazole derivative that was screened to help combat the unmet needs in TB treatment. The compound is a mycolic acid biosynthesis inhibitor found to be free of mutagenicity and to possess highly potent activity against TB, including MDR-TB, as shown by its exceptionally low minimum inhibitory concentration (MIC) range of 0.006–0.024 μg/ml in vitro and highly effective therapeutic activity at low doses in vivo. Additionally, the results of the post-antibiotic effect of OPC-67683 on intracellular Mycobacterium tuberculosis showed the agent to be highly and dose-dependently active also against intracellular M. tuberculosis H37Rv after a 4-h pulsed exposure, and this activity at a concentration of 0.1 μg/ml was similar to that of the first-line drug rifampicin (RFP) at a concentration of 3 μg/ml. The combination of OPC-67683 with RFP and pyrazinamide (PZA) exhibited a remarkably quicker eradication (by at least 2 mo) of viable TB bacilli in the lung in comparison with the standard regimen consisting of RFP, isoniazid (INH), ethambutol (EB), and PZA. Furthermore, OPC-67683 was not affected by nor did it affect the activity of liver microsome enzymes, suggesting the possibility for OPC-67683 to be used in combination with drugs, including anti-retrovirals, that induce or are metabolized by cytochrome P450 enzymes. We concluded that based on these properties OPC-67683 has the potential to be used as a TB drug to help combat the unmet needs in TB treatment. A nitro-dihydro-imidazooxazole derivative was shown to have the potential for use against tuberculosis. One-third of the world's population is infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB). Most infected people are healthy—the bacteria can remain latent for years, hidden within cells in the body. However, every year 8 million people develop active TB, a chronic disease that usually affects the lungs, and 2 million people die. For most of the second half of the 20th century, TB was in decline because of the powerful antibiotics that were developed from the 1940s onwards. The standard treatment for TB—four antibiotics that have to be taken several times a week for at least six months to flush out any latent M. tuberculosis bacteria—was introduced in the late 1970s and saved many lives. Recently, however, efforts to eradicate TB have been set back by the HIV/AIDS epidemic—people with damaged immune systems are very susceptible to TB—and the emergence of multi-drug resistant (MDR) bacteria. The treatment for TB is long and unpleasant, and patients who develop MDR-TB have to be treated with second-line drugs that are less effective, more expensive, and more toxic. In addition, for people infected with both HIV and TB, some antiretroviral and anti-TB drugs cannot be used at the same time. Many drugs are either activated or removed by enzymes in the liver, so combinations of these two classes of drugs sometimes alter liver function in a way that causes clinical problems. There is, therefore, an urgent need for new, effective anti-TB drugs that attack M. tuberculosis in a different way than do existing drugs. Such drugs should ideally be active against MDR M. tuberculosis, work quickly at low doses, be active against latent bacteria, and have minimal effects on the liver so that they can be used in patients co-infected with HIV. In this study, the researchers investigated a chemical called OPC-67683. The researchers identified a compound that inhibited the production of mycolic acid—an essential component of the cell wall of M. tuberculosis—and they tested its ability to kill the organism. They then tested in detail its ability to inhibit bacterial growth in dishes of antibiotic-sensitive and MDR M. tuberculosis and isolates from patients. OPC-67683 inhibited the growth of all these bugs at lower concentrations than the four antibiotics used in the standard TB treatment. It also killed bacteria hidden within human cells as well as or better than these drugs. Next, the researchers treated mice infected with M. tuberculosis with OPC-67683. They found that it reduced the number of bacteria in the lungs of both normal and immunocompromised mice at lower concentrations than the standard drugs. Furthermore, when combined with two of the standard drugs, it reduced the time taken to clear bacteria from the lungs by the standard drug regimen by two months. Finally, the researchers showed that OPC-67683 had no effects on the liver enzymes that metabolize antiretrovirals, and, conversely, that the activity of OPC-67683 was not affected by liver enzymes. Thus, this agent is unlikely to cause clinical problems or lose its efficacy in HIV patients who are receiving antiretroviral drugs. These results from laboratory and animal experiments suggest that OPC-67683 could possibly fulfill the criteria for a new anti-TB drug. OPC-67683 is active against MDR-TB. It is also active against intracellular TB, which the authors postulate could be a positive link with the effective treatment of latent TB, and it works quickly in animals when combined with existing anti-TB drugs. Importantly, it also disables M. tuberculosis in a unique way and does not appear to have any major effects on the liver that might stop it from being used in combination with antiretrovirals. All these preclinical characteristics now need to be checked in people—many drugs do well in preclinical studies but fail in patients. These clinical studies need to be expedited given the upsurge in TB, and, write the researchers, OPC-67683 needs to be tested in combination with both conventional drugs and other new drugs so that the best regimen of new drugs for the treatment of TB can be found as soon as possible. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030466. US National Institute of Allergy and Infectious Diseases patient fact sheet on tuberculosis US Centers for Disease Control and Prevention information on tuberculosis MedlinePlus encyclopedia entry on tuberculosis NHS Direct Online patient information on tuberculosis from the UK National Health Service World Health Organization information on the global elimination of tuberculosis Global Alliance for TB Drug Development information on why new TB drugs are needed
登录
查看更多内容
影响因子：
1.8
作者：
BALDWIN, SJ;BLOOMER, JC;CHENERY, RJ
通讯作者：
CHENERY, RJ
影响因子：
5.1
作者：
Li, AP;Reith, MK;Cheng, LK
通讯作者：
Cheng, LK
DOI：
10.1073/pnas.0508392103
发表时间：
2006-01-10
影响因子：
11.1
作者：
Manjunatha, UH;Boshoff, H;Barry, CE
通讯作者：
Barry, CE
DOI：
10.1111/j.1365-2125.1990.tb03686.x
发表时间：
1990-06-01
影响因子：
3.4
作者：
SESARDIC, D;BOOBIS, AR;DAVIES, DS
通讯作者：
DAVIES, DS
影响因子：
120.7
作者：
Dye, C;Scheele, S;Raviglione, RC
通讯作者：
Raviglione, RC