Ramasesh N, Krahenbuhl J L, Hastings R C
Laboratory Research Branch, Gillis W. Long Hansen's Disease Center, Carville, Louisiana 70721.
Antimicrob Agents Chemother. 1989 May;33(5):657-62. doi: 10.1128/AAC.33.5.657.
Mycobacterium leprae synthesizes large quantities of a specific phthiocerol-containing phenolic glycolipid in vivo. We have shown earlier that viable M. leprae readily incorporates radiolabeled palmitic acid into phenolic glycolipid I when residing in cultured macrophages in vitro and that this process is inhibited by the antileprosy drug rifampin. In the present paper we report that application of this observation to the rapid evaluation of over 25 antimicrobial agents for potential antileprosy activity in vitro. All the known antileprosy drugs rifampin, dapsone, clofazimine, and ethionamide inhibited phenolic glycolipid I synthesis. Rifabutin, a spiropiperidyl derivative of rifamycin, also reported to be active in the mouse model, was very effective. Interestingly, the macrolides erythromycin, clarithromycin, and roxithromycin were also found to be active in this system, while D-cycloserine and other cell wall synthesis inhibitors showed no effect. Many of the compounds found to be active in this system have been reported to be effective in vivo in mice. This correlation lends support to the feasibility of using phenolic glycolipid I synthesis for the rapid evaluation of new drugs against leprosy.
麻风分枝杆菌在体内合成大量特定的含结核硬脂醇的酚糖脂。我们之前已经表明，活的麻风分枝杆菌在体外培养的巨噬细胞中时，能很容易地将放射性标记的棕榈酸掺入酚糖脂I中，并且这个过程会被抗麻风病药物利福平抑制。在本文中，我们报告了将这一观察结果应用于快速评估25种以上抗菌剂在体外的潜在抗麻风病活性。所有已知的抗麻风病药物利福平、氨苯砜、氯法齐明和乙硫异烟胺都抑制酚糖脂I的合成。利福布汀，一种利福霉素的螺哌啶衍生物，据报道在小鼠模型中也有活性，非常有效。有趣的是，大环内酯类药物红霉素、克拉霉素和罗红霉素在这个系统中也被发现有活性，而D-环丝氨酸和其他细胞壁合成抑制剂则没有效果。在这个系统中发现有活性的许多化合物据报道在小鼠体内也有效。这种相关性支持了利用酚糖脂I合成来快速评估抗麻风病新药的可行性。
