RECOGNITION OF MULTIPLE EFFECTS OF ETHAMBUTOL ON METABOLISM OF MYCOBACTERIAL CELL-ENVELOPE
RECOGNITION OF MULTIPLE EFFECTS OF ETHAMBUTOL ON METABOLISM OF MYCOBACTERIAL CELL-ENVELOPE
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DOI：
10.1128/aac.39.3.694
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发表时间：
1995-03-01
影响因子：
4.9
通讯作者：
MCNEIL, MR
中科院分区：
文献类型：
--
作者：
DENG, LY;MIKUSOVA, K;MCNEIL, MR
已知乙胺丁醇可快速抑制分枝杆菌细胞壁核心聚合物阿拉伯半乳聚糖（K. Takayama和J.O.吉尔本抗菌剂探员Chemother三十三：1493-1499，1989），这种作用得到证实，并且还显示乙胺丁醇抑制脂阿拉伯甘露聚糖的阿拉伯聚糖的生物合成，脂阿拉伯甘露聚糖是与细胞壁核心非共价结合的脂多糖。与细胞壁核心阿拉伯聚糖（其被乙胺丁醇完全抑制）相反，脂阿拉伯甘露聚糖的阿拉伯聚糖的合成仅受到部分影响，证明了对两个部位中阿拉伯聚糖合成的不同作用。乙胺丁醇对细胞壁生物合成的作用的进一步研究揭示，细胞壁核心中半乳聚糖的合成被药物强烈抑制。此外，乙胺丁醇处理导致分枝杆菌细胞壁中存在的阿拉伯糖残基的裂解;在向生长的分枝杆菌培养物中加入药物后1小时，细胞壁核心中超过50%的阿拉伯聚糖从壁中除去。相反，在乙胺丁醇处理期间，半乳聚糖不从细胞壁中释放，阿拉伯糖基释放酶的天然功能仍然未知，但其作用与乙胺丁醇治疗期间合成的抑制相结合导致分枝杆菌细胞壁的严重破坏。因此，乙胺丁醇诱导的细胞壁损伤为乙胺丁醇与其他化疗剂的已知协同作用提供了现成的分子解释。乙胺丁醇最初的直接作用仍有待阐明。
Ethambutol is known to rapidly inhibit biosynthesis of the arabinan component of the mycobacterial cell wall core polymer, arabinogalactan (K. Takayama and J. O. Kilburn, Antimicrob. Agents Chemother. 33:1493-1499, 1989), This effect was confirmed, and it was also shown that ethambutol inhibits biosynthesis of the arabinan of lipoarabinomannan, a lipopolysaccharide noncovalently associated with the cell wall core, In contrast to cell wall core arabinan, which is completely inhibited by ethambutol, synthesis of the arabinan of lipoarabinomannan was only partially affected, demonstrating a differential effect on arabinan synthesis in the two locales, Further studies of the effect of ethambutol on cell wall biosynthesis revealed that the synthesis of galactan in the cell wall core is strongly inhibited by the drug, In addition, ethambutol treatment resulted in the cleavage of arabinosyl residues present in the mycobacterial cell wall; more than 50% of the arabinan in the cell wall core was removed from the wall 1 h after addition of the drug to growing mycobacterial cultures, In contrast, galactan,vas not released from the cell wall during ethambutol treatment, The natural function of the arabinosyl-releasing enzyme remains unknown, but its action in combination with inhibition of synthesis during ethambutol treatment results in severe disruption of the mycobacterial cell wall, Accordingly, ethambutol-induced damage to the cell wall provides a ready molecular explanation for the known synergetic effects of ethambutol with other chemotherapeutic agents, Nevertheless, the initial direct effect of ethambutol remains to be elucidated.