Reconstitution of S. aureus lipoteichoic acid synthase activity identifies Congo red as a selective inhibitor,Journal of the American Chemical Society

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Reconstitution of S. aureus lipoteichoic acid synthase activity identifies Congo red as a selective inhibitor
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-01-09 , DOI: 10.1021/jacs.7b11704
Christopher R Vickery ₁ , B McKay Wood ₁ , Heidi G Morris ₁ , Richard Losick ₂ , Suzanne Walker ₁

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Lipoteichoic acid (LTA) is an anionic surface polymer that is essential for normal growth of Staphylococcus aureus, making the LTA polymerase, LTA synthase (LtaS), a proposed drug target for combating Staphylococcal infections. LtaS is a polytopic membrane protein with five membrane-spanning helices and an extracellular domain, and it uses phosphatidylglycerol to assemble a glycerol phosphate chain on a glycosylated diacylglycerol membrane anchor. We report here the first reconstitution of LtaS polymerization activity and show that the azo dye Congo red inhibits this enzyme both in vitro and in cells. Related azo dyes and the previously reported LtaS inhibitor 1771 have weak or no in vitro inhibitory activity. Synthetic lethality with mutant strains known to be nonviable in the absence of LTA confirms selective inhibition by Congo red. As the only validated LtaS inhibitor, Congo red can serve as a probe to understand how inhibiting lipoteichoic acid biosynthesis affects cell physiology and may also guide the discovery of more potent inhibitors for use in treating S. aureus infections.

中文翻译：

金黄色葡萄球菌脂磷壁酸合酶活性的重建鉴定刚果红为选择性抑制剂

脂磷壁酸 (LTA) 是一种阴离子表面聚合物，对于金黄色葡萄球菌的正常生长至关重要，使得 LTA 聚合酶、LTA 合酶 (LtaS) 成为对抗葡萄球菌感染的拟议药物靶点。 LtaS 是一种多胞膜蛋白，具有五个跨膜螺旋和一个胞外结构域，它使用磷脂酰甘油在糖基化二酰基甘油膜锚上组装磷酸甘油链。我们在这里报告了 LtaS 聚合活性的首次重建，并表明偶氮染料刚果红在体外和细胞内抑制这种酶。相关偶氮染料和之前报道的LtaS抑制剂1771体外抑制活性较弱或无。已知在缺乏 LTA 的情况下无法存活的突变株的综合致死率证实了刚果红的选择性抑制。作为唯一经过验证的 LtaS 抑制剂，刚果红可以作为探针来了解抑制脂磷壁酸生物合成如何影响细胞生理学，并且还可以指导发现用于治疗金黄色葡萄球菌感染的更有效的抑制剂。

更新日期：2018-01-09

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