14 NSFBIO:Identifying Mechanisms for Environmental Adaptation in CMNR Bacteria: A Systems Analysis of GeneRegulation of AlternativeSubstrateMetabolism

14 NSFBIO：识别 CMNR 细菌环境适应机制：替代底物代谢基因调控的系统分析

• 批准号: BB/N01314X/1
• 负责人: Apoorva Bhatt
• 金额: $ 54.2万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN01314X%2F1
• 关键词: 14; NSFBIO; Identifying; Mechanisms; Environmental

Members of the Corynebacteria-Mycobacteria-Nocardia-Rhodococcus (CMNR) group of bacteria are best recognized for their impact on human health and they include the causative agent of tuberculosis (TB; Mycobacterium tuberculosis), leprosy (Mycobacterium leprae) and diphtheria (Corynebacterium diptheriae). However, many members of this group are also of great significance to agriculture, biotechnology, and environmental issues. CMNR bacteria also include animal (Mycobacterium bovis, Rhodococcus equi, and species of Corynebacteria and Nocardia) and plant (Rhodococcus) pathogens with a broad host range. They also are widely used in industry. Examples include Corynebacterium glutamicum which is used for large-scale manufacturing of amino acids such as L-glutamate and bacteria that are known to accumulate triacyglycerols (TAGs), oils that are the direct building blocks for biodiesel. Furthermore, some CMNR bacteria are also used for a process termed bioremediation due to their ability to break down harmful and persistent pollutants in the environment. A common theme among the CMNR bacteria is a lipid-rich cell envelope that contains fatty acids and lipids that are distinct and not found in other bacteria. This complexity is reflected in the relatively large proportion of lipid metabolism related genes in the genomes of these bacteria. The diversity of habitats colonized by CMNR bacteria is rooted in their ability to adapt to new environments by dynamically altering the composition of complex fatty acids in their unique cell envelope. This proposal will test the hypothesis that depending on the environment and available substrates, the CMNR bacteria selectively alter the composition of their cell envelope. We propose that the bacteria achieve by using expanded families of genes involved in the uptake and biosynthesis of cell envelope 'building blocks'. To elucidate how CMNR bacteria achieve this we will first test the ability of a model CMNR bacterium, Mycobacterium smegmatis, to grow on different substrates that can potentially act as 'building blocks'. We will select growth conditions that lead to cell envelope alterations and determine the transciptome (a global picture of the levels to which genes are expressed) of M. smegmatis growing under the select conditions. The information obtained from these studies will then be analysed using in-house computational tools (a program called EGRIN 2.0) to generate models of gene regulatory networks. In other words, we will 'reverse engineer' these networks in the model bacterium. This model will subsequently allow us, by comparing published genomes, to characterize common and unique regulatory mechanisms across CMNR bacteria. Model predictions will be tested by analyzing consequences of specific gene deletions on cell envelope composition of representative CMNR bacteria under relevant conditions. This inter-institutional proposal combines the complementary expertise of the US and UK based research groups. The systems biology expertise of the US-based PI with the UK-based PI's expertise in characterizing CMNR bacteria lipid metabolism and cell envelope biochemistry will allow us to address the fundamental and biotechnologically important question of how CMNR bacteria adapt to new environments.

棒状杆菌-分枝杆菌-诺卡德-红球菌（ccmr）细菌群的成员因其对人类健康的影响而得到最好的认识，它们包括结核病（结核分枝杆菌）、麻风病（麻风分枝杆菌）和白喉（白喉棒状杆菌）的病原体。然而，这个群体的许多成员也对农业、生物技术和环境问题具有重要意义。cmrr细菌还包括具有广泛宿主范围的动物（牛分枝杆菌、马红球菌以及棒状杆菌和诺卡菌）和植物（红球菌）病原体。它们也广泛应用于工业。例子包括用于大规模生产氨基酸（如l -谷氨酸）的谷氨酸棒状杆菌和已知会积累甘油三酯（标签）的细菌，甘油三酯是生物柴油的直接组成部分。此外，一些cmrr细菌也被用于称为生物修复的过程，因为它们能够分解环境中的有害和持久性污染物。cmrr细菌的一个共同主题是富含脂质的细胞包膜，其中含有脂肪酸和脂质，这些脂肪酸和脂质是独特的，在其他细菌中没有发现。这种复杂性反映在这些细菌基因组中相对较大比例的脂质代谢相关基因上。cmrr细菌定植栖息地的多样性源于它们通过动态改变其独特细胞包膜中复合脂肪酸的组成来适应新环境的能力。这一提议将验证一个假设，即根据环境和可利用的底物，cmrr细菌选择性地改变其细胞包膜的组成。我们提出，细菌通过使用参与细胞包膜“构建块”的摄取和生物合成的扩展基因家族来实现。为了阐明CMNR细菌是如何实现这一目标的，我们将首先测试一种模型CMNR细菌——耻垢分枝杆菌在不同基质上生长的能力，这些基质可能作为“构建块”。我们将选择导致细胞包膜改变的生长条件，并确定在选择条件下生长的耻垢分枝杆菌的转录组（基因表达水平的全局图）。从这些研究中获得的信息随后将使用内部计算工具（一个名为EGRIN 2.0的程序）进行分析，以生成基因调控网络模型。换句话说，我们将在模型细菌中“逆向工程”这些网络。该模型随后将允许我们通过比较已发表的基因组来表征cmrr细菌的共同和独特调节机制。通过分析特定基因缺失对相关条件下代表性cmrr细菌包膜组成的影响，对模型预测进行检验。这一机构间提案结合了美国和英国研究小组的互补专业知识。美国PI的系统生物学专业知识与英国PI在表征CMNR细菌脂质代谢和细胞包膜生物化学方面的专业知识将使我们能够解决CMNR细菌如何适应新环境的基本和生物技术重要问题。

项目成果

MtrA modulates Mycobacterium tuberculosis cell division in host microenvironments to mediate intrinsic resistance and drug tolerance.

• DOI: 10.1016/j.celrep.2023.112875
• 发表时间: 2023-08-29
• 期刊: Cell reports
• 影响因子: 8.8

Mycobacterium abscessus biofilms produce an extracellular matrix and have a distinct mycolic acid profile.

脓肿分枝杆菌生物膜产生细胞外基质并具有独特的分枝菌酸特征。

• DOI: 10.1016/j.tcsw.2021.100051
• 发表时间: 2021-12
• 期刊: Cell surface (Amsterdam, Netherlands)
• 作者: Dokic A;Peterson E;Arrieta-Ortiz ML;Pan M;Di Maio A;Baliga N;Bhatt A
• 通讯作者: Bhatt A

Identification of a Desaturase Involved in Mycolic Acid Biosynthesis in Mycobacterium smegmatis.

• DOI: 10.1371/journal.pone.0164253
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Singh A;Varela C;Bhatt K;Veerapen N;Lee OY;Wu HH;Besra GS;Minnikin DE;Fujiwara N;Teramoto K;Bhatt A
• 通讯作者: Bhatt A

The mycobacterial desaturase DesA2 is associated with mycolic acid biosynthesis.

• DOI: 10.1038/s41598-022-10589-y
• 发表时间: 2022-04-28
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Bailo, Rebeca;Radhakrishnan, Anjana;Singh, Albel;Nakaya, Makoto;Fujiwara, Nagatoshi;Bhatt, Apoorva
• 通讯作者: Bhatt, Apoorva

MadR mediates acyl CoA-dependent regulation of mycolic acid desaturation in mycobacteria.

• DOI: 10.1073/pnas.2111059119
• 发表时间: 2022-02-22
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Cooper C;Peterson EJR;Bailo R;Pan M;Singh A;Moynihan P;Nakaya M;Fujiwara N;Baliga N;Bhatt A
• 通讯作者: Bhatt A