Institut für Bio- und Geowissenschaften, IBG-1: Biotechnologie, Forschungszentrum Jülich, 52425 Jülich, Germany.
BMC Biol. 2013 Dec 30;11:122. doi: 10.1186/1741-7007-11-122.
The development of new drugs against tuberculosis and diphtheria is focused on disrupting the biogenesis of the cell wall, the unique architecture of which confers resistance against current therapies. The enzymatic pathways involved in the synthesis of the cell wall by these pathogens are well understood, but the underlying regulatory mechanisms are largely unknown.
Here, we characterize IpsA, a LacI-type transcriptional regulator conserved among Mycobacteria and Corynebacteria that plays a role in the regulation of cell wall biogenesis. IpsA triggers myo-inositol formation by activating ino1, which encodes inositol phosphate synthase. An ipsA deletion mutant of Corynebacterium glutamicum cultured on glucose displayed significantly impaired growth and presented an elongated cell morphology. Further studies revealed the absence of inositol-derived lipids in the cell wall and a complete loss of mycothiol biosynthesis. The phenotype of the C. glutamicum ipsA deletion mutant was complemented to different extend by homologs from Corynebacterium diphtheriae (dip1969) and Mycobacterium tuberculosis (rv3575), indicating the conserved function of IpsA in the pathogenic species. Additional targets of IpsA with putative functions in cell wall biogenesis were identified and IpsA was shown to bind to a conserved palindromic motif within the corresponding promoter regions. Myo-inositol was identified as an effector of IpsA, causing the dissociation of the IpsA-DNA complex in vitro.
This characterization of IpsA function and of its regulon sheds light on the complex transcriptional control of cell wall biogenesis in the mycolata taxon and generates novel targets for drug development.
针对结核病和白喉的新型药物的研发重点在于破坏细胞壁的生物发生，其独特的结构赋予了它们对现有疗法的抗性。这些病原体合成细胞壁所涉及的酶途径已经得到很好的理解，但潜在的调控机制在很大程度上仍不清楚。
在这里，我们描述了 IpsA，这是一种在分枝杆菌和棒状杆菌中保守的 LacI 型转录调节因子，它在细胞壁生物发生的调控中发挥作用。IpsA 通过激活编码肌醇磷酸合酶的 ino1 触发肌醇的形成。在葡萄糖上培养的谷氨酸棒状杆菌的 ipsA 缺失突变体显示出明显的生长受损和伸长的细胞形态。进一步的研究表明，细胞壁中没有肌醇衍生的脂质，并且完整的分枝菌防御素生物合成缺失。C. glutamicum 的 ipsA 缺失突变体的表型在不同程度上被来自白喉棒状杆菌（dip1969）和结核分枝杆菌（rv3575）的同源物所弥补，这表明 IpsA 在致病性物种中具有保守的功能。还确定了 IpsA 的其他潜在的细胞壁生物发生靶标，并表明 IpsA 与相应启动子区域内保守的回文基序结合。肌醇被鉴定为 IpsA 的效应物，导致 IpsA-DNA 复合物在体外解离。
对 IpsA 功能及其调控子的表征揭示了分枝杆菌属生物细胞壁生物发生的复杂转录调控，并为药物开发生成了新的靶标。
