Untangling the Inner Workings of the Mycobacterial Cell Envelope

项目摘要 分枝杆菌是许多细菌规则的例外。它们的细胞结构和生长方式 共同的假设。此外，他们特殊的细胞生物学被认为是特殊行为的基础 例如对药物的耐受性。药物耐受性对分枝杆菌是普遍的，但特别与分枝杆菌相关。 根除致病物种，如导致结核病的结核分枝杆菌。独特的 分支杆菌的特征可以为更有效地针对它们的感染提供有吸引力的途径。 例如，它们的细胞被膜是一种多层细胞结构，是细菌中最复杂的结构之一。 分枝杆菌是分枝杆菌界的一个分支，它有助于分枝杆菌对抗生素的固有耐药性。然而， 细胞膜在生长和分裂过程中是如何形成的。特别是，人们对 组装的外部膜状屏障称为菌膜，这是一个定义的功能， 分枝杆菌由于其不寻常的组成和极端的疏水性。这项建议的理由是， 揭示这些基本原理对于理解分枝杆菌在挑战性环境中的生存至关重要。 他们遇到的环境。这项研究计划的目的是揭示机制， 菌膜生物发生和细胞伸长的联系。该提案涉及三个问题： 问1：分枝杆菌如何将脂质输出到菌膜？ 问题2：分枝杆菌如何合成多层细胞包膜并实现局部生长 从他们的极点？ 问题3：我们如何识别分枝杆菌细胞包膜内的基本过程的机制？ PI和她的团队将通过微生物学，生物化学和生物化学的结合来解决这些问题。 化学生物学一个合作网络支持这个项目。该项目的影响是提供（1） 合理靶向细胞包膜生物发生用于抗感染治疗的机会，以及（2） 需要研究分枝杆菌细胞包膜蛋白的工具。

PROJECT SUMMARY Mycobacteria are the exception to many rules for bacteria. Their cellular structure and the way they grow defy common assumptions. Moreover, their exceptional cell biology is believed to underlie exceptional behaviors such as tolerance to drugs. Drug tolerance is general to mycobacteria, but is especially relevant to the eradication of pathogenic species such as Mycobacterium tuberculosis, which causes tuberculosis. The unique characteristics of mycobacteria could offer attractive avenues for more effectively targeting them in infection. For example, their cell envelope is a multilayer cellular structure that is one of the most complex in the bacterial kingdom and contributes to the inherent resistance of mycobacteria to antibiotics. However, very little is known about how the cell envelope is made during growth and division. In particular very little is known about the assembly of the outer membrane-like barrier known as the mycomembrane, which is a defining feature of mycobacteria due to its unusual composition and extreme hydrophobicity. The rationale of this proposal is that uncovering such fundamentals is essential to understanding mycobacterial survival in the challenging environments that they encounter. The objective of this research program is to uncover mechanisms of mycomembrane biogenesis and the connections to cell elongation. The proposal addresses three questions: Q1: How do mycobacteria export lipids to the mycomembrane? Q2: How do mycobacteria synthesize the multiple layers of the cell envelope and achieve localized growth from their poles? Q3: How do we identify the machinery for essential processes within the mycobacterial cell envelope? The PI and her team will address these questions through a combination of microbiology, biochemistry, and chemical biology. A network of collaborations supports this program. The impact of this project is to provide (1) opportunities for the rational targeting of cell envelope biogenesis for anti-infective therapy and (2) much- needed tools to investigate mycobacterial cell envelope proteins.