The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways

结核分枝杆菌细胞包膜：揭示复杂的细胞壁组装、降解和再循环途径

• 批准号: MR/S000542/1
• 负责人: Gurdyal Besra
• 金额: $ 219.27万
• 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: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS000542%2F1
• 关键词: Mycobacterium; tuberculosis; Cell; Envelope; unravelling

Tuberculosis (TB) is a bacterial infection caused by the tubercle bacillus. Worldwide TB remains the leading bacterial cause of mortality and morbidity. In 2016, the WHO reported 10.4 million new cases of TB, with 1.7 million people dying from TB that year. Predominantly a disease of poverty, TB affects young adults in their productive years and hence also carries a large economic burden. This picture is highlighted by populations living in low and middle income countries (LMICs), where the burden of TB is most prevalent, with high morbidity and mortality rates, such as in India (510,000 p.a.), Indonesia (130,000 p.a.), China (38,000 p.a.), Nigeria (240,000 p.a.) and South Africa (97,000 p.a.). Therefore, introducing a new TB drug onto the market and its impact upon the health and global economy for these LMICs represents an urgent healthcare challenge, which needs to be viewed on at least a 10-15-year timescale. Our application seeks support for research into the cell envelope of Mycobacterium tuberculosis. All bacterial cells are enclosed in a cell wall or cell envelope. This is a dense layer of covalently-linked molecules around the cellular membrane, protecting the organism from its immediate environment. The cell wall of M. tuberculosis is very distinctive, differing from other bacteria in containing an exceptional amount of unique lipids (fats) and sugars. This high content of lipids and sugars makes the M. tuberculosis cell wall impermeable to most antibiotics. At the same time, the organism is very vulnerable if the cell wall has defects. Therefore, some existing TB antibiotics interfere with the synthesis of cell wall components, and for the same reason many TB drug development efforts focus on the cell wall. Our research will concentrate on learning more about the biology surrounding the M. tuberculosis cell wall. Firstly, building on our previous studies on lipid synthesis, we will examine enzyme systems that degrade lipids. This is important because M. tuberculosis has limited access to nutrients and has developed strategies to recycle molecular components for new uses. Secondly, we will study how M. tuberculosis assembles sugar-like polymers, such as arabinogalactan and the key virulence factor, lipoarabinomannan, outside of its cell membrane. Our third aim is to understand a range of enzymes that appear to play a role in remodelling peptidoglycan, a molecular 'mesh' that is commonly found in bacteria, but has distinct features in M. tuberculosis. Fourthly, we will use small-scale mechanical probes to clarify how the bacteria are constructed and help explain how interactions of the key building blocks influence virulence. In characterising the enzymes and proteins involved in these biological processes, we aim to find proteins that are 'good' drug targets, for instance because they are unique to this organism or because the cell cannot compensate when they are inactivated by a drug. To achieve this goal, our research will rest on three fundamental research pillars: 1) the identification of essential mycobacterial proteins and how the interaction between the protein target and an inhibitor can be improved; 2) determine how and why these compounds kill bacilli, their mode of action; and 3) develop our partnerships with laboratories in LMICs, such as the Institute of Materia Medica (IMM), Beijing, China and the Indian Institute of Science (IISc), Bangalore, India, and through our industrial links with GlaxoSmithKline Diseases of the Developing World (GSK DDW), Madrid, Spain, develop drug discovery projects to turns 'hits' into 'leads' and ultimately into new TB-drugs. Thus, this proposal offers the opportunity to tackle a range of fundamental questions about an organism that has puzzled microbiologists ever since its discovery by Robert Koch in 1882, that can be used to treat a debilitating disease which represents one of the most pressing healthcare challenges for Society in the 21st Century.

结核病（TB）是一种由结核杆菌引起的细菌感染。在世界范围内，结核病仍然是导致死亡和发病的主要细菌原因。2016年，世卫组织报告了1040万新发结核病病例，当年有170万人死于结核病。结核病主要是一种贫困疾病，影响到处于生产年龄的年轻人，因此也带来了巨大的经济负担。这一情况在低收入和中等收入国家（LMICs）的人群中尤为突出，这些国家的结核病负担最为普遍，发病率和死亡率都很高，例如印度（每年51万人）、印度尼西亚（每年13万人）、中国（每年3.8万人）、尼日利亚（每年24万人）和南非（每年9.7万人）。因此，向市场推出一种新的结核病药物及其对这些中低收入国家的卫生和全球经济的影响是一项紧迫的卫生保健挑战，需要至少在10-15年的时间尺度上加以考虑。我们的申请寻求支持研究结核分枝杆菌的细胞包膜。所有的细菌细胞都包裹在细胞壁或细胞膜中。这是一层紧密的共价键分子围绕在细胞膜上，保护生物体免受直接环境的影响。结核分枝杆菌的细胞壁非常独特，与其他细菌不同，它含有大量独特的脂质（脂肪）和糖。这种高含量的脂质和糖使得结核分枝杆菌细胞壁不被大多数抗生素渗透。同时，如果细胞壁有缺陷，生物体是非常脆弱的。因此，一些现有的结核病抗生素会干扰细胞壁成分的合成，出于同样的原因，许多结核病药物的开发工作都集中在细胞壁上。我们的研究将集中于更多地了解围绕结核分枝杆菌细胞壁的生物学。首先，在我们之前对脂质合成的研究的基础上，我们将研究降解脂质的酶系统。这很重要，因为结核分枝杆菌获得营养物质的途径有限，并且已经制定了回收分子成分用于新用途的策略。其次，我们将研究结核分枝杆菌如何在其细胞膜外组装糖样聚合物，如阿拉伯半乳聚糖和关键毒力因子脂阿拉伯糖甘露聚糖。我们的第三个目标是了解一系列似乎在重塑肽聚糖中发挥作用的酶，肽聚糖是细菌中常见的一种分子“网”，但在结核分枝杆菌中具有独特的特征。第四，我们将使用小型机械探针来阐明细菌是如何构建的，并帮助解释关键构建块的相互作用如何影响毒力。在描述这些生物过程中涉及的酶和蛋白质时，我们的目标是找到“好的”药物靶标蛋白质，例如，因为它们是这种生物体所特有的，或者因为细胞在药物灭活时无法补偿它们。为了实现这一目标，我们的研究将建立在三个基础研究支柱上：1)鉴定必需的分枝杆菌蛋白，以及如何改善蛋白靶点与抑制剂之间的相互作用；2)确定这些化合物如何以及为什么杀死杆菌，它们的作用方式；3)与中低收入国家的实验室建立合作伙伴关系，如中国北京的药物研究所（IMM）和印度班加罗尔的印度科学研究所（IISc），并通过我们与西班牙马德里的葛兰素史克发展中国家疾病研究所（GSK DDW）的工业联系，开发药物发现项目，将“热门药物”转化为“先导药物”，并最终开发出新的结核病药物。因此，该提案提供了解决一系列关于微生物的基本问题的机会，这些问题自1882年被罗伯特·科赫发现以来一直困扰着微生物学家，这些问题可以用来治疗一种衰弱性疾病，这种疾病是21世纪社会最紧迫的医疗挑战之一。

项目成果

Mycobacterial drug discovery.

• DOI: 10.1039/d0md00261e
• 发表时间: 2020-11-06
• 期刊: RSC medicinal chemistry
• 影响因子: 4.1
• 作者: Abrahams KA;Besra GS
• 通讯作者: Besra GS

Antibiotics and resistance: the two-sided coin of the mycobacterial cell wall.

• DOI: 10.1016/j.tcsw.2020.100044
• 发表时间: 2020-12
• 期刊: Cell surface (Amsterdam, Netherlands)
• 作者: Batt SM;Burke CE;Moorey AR;Besra GS
• 通讯作者: Besra GS

Synthesis and recycling of the mycobacterial cell envelope.

• DOI: 10.1016/j.mib.2021.01.012
• 发表时间: 2021-04
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Abrahams KA;Besra GS
• 通讯作者: Besra GS

DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid.

• DOI: 10.1038/s41467-023-39300-z
• 发表时间: 2023-06-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Abrahams KA;Batt SM;Gurcha SS;Veerapen N;Bashiri G;Besra GS
• 通讯作者: Besra GS

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