Interplay between the Mtb electron transport chain and carbon metabolism

Mtb 电子传递链与碳代谢之间的相互作用

• 批准号: 10512057
• 负责人: ADRIE JC STEYN
• 金额: $ 39.91万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-07 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512057
• 关键词: Aerobic Bacteria; Antimycobacterial Agents; Back; Binding; Bioenergetics; Carbon; Catabolism; Cause of Death; Cessation of life; Citric Acid Cycle; Clinical; Communication; Complement; Complex; Cytochromes; Data; Development; Disease; Drug Combinations; Drug Compounding; Drug Targeting; Drug Tolerance; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Electron Transport; Energy Metabolism; Etiology; Excretory function; Exposure to; Functional disorder; Genes; Genetic; Glucose; Glycolysis; Glycolysis Inhibition; Goals; Growth; Health; Homeostasis; Immune; Immune response; Infectious Agent; Knowledge; Measures; Metabolic; Metabolism; Mycobacterium tuberculosis; Nutrient; Outcome; Oxaloacetates; Oxidative Phosphorylation; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phenothiazines; Phosphorylation; Predisposition; Primary Infection; Process; Production; Proton-Motive Force; Pyruvate; Research; Resolution; Respiration; Route; Scientist; Series; Shunt Device; Source; Spirometry; Sterilization; Succinates; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Tuberculosis; biological adaptation to stress; cell killing; differential expression; environmental change; experimental study; extracellular; flexibility; genome sequencing; glyoxylate; in vivo; inhibitor; innovation; interest; liquid chromatography mass spectrometry; metabolomics; mutant; mycobacterial; new technology; novel therapeutics; pathogenic microbe; pharmacologic; pressure; prevent; preventive intervention; programs; respiratory; response; stable isotope; transcriptome sequencing; tuberculosis drugs; whole genome

Tuberculosis, caused by the etiological agent Mycobacterium tuberculosis (Mtb), is the leading cause of death worldwide from a curable infectious agent and is becoming a major concern due to the spread of drug resistant Mtb strains. Notably, Mtb can persist in a dormant, drug resistant state, sometimes reactivating to cause TB decades after the primary infection. Currently, there is strong interest in exploiting oxidative phosphorylation (OXPHOS) as a metabolic target for new anti-TB drugs and drug combinations. In this regard, there are several antimycobacterial drugs that target the Mtb electron transport chain (ETC), including bedaquiline (the first new TB drug in ~40 years), Q203, clofazimine, and phenothiazines. However, how inhibition of respiratory complexes in the ETC leads to effective killing has yet to be established. We believe there is a critical gap in our understanding of how OXPHOS communicates with central carbon catabolism in response to changing environmental fuel sources to survive the host immune response and anti-TB drug therapy. Our long-term goal is to define the bioenergetic mechanisms that enable Mtb to survive within the host in a dormant, drug resistant state. In this proposal, our central hypothesis is that the interplay between the Mtb ETC and central carbon catabolism prevents effective killing by anti-TB drugs. To test this hypothesis, we have established a series of specific aims to determine how OXPHOS-generated ATP modulates central carbon catabolism and succinate excretion to maintain metabolic homeostasis, examine the mechanisms whereby simultaneous inhibition of OXPHOS and glycolysis kills Mtb, and test the hypothesis that bioenergetic homeostasis in clinical strains of Mtb contributes to drug tolerance. We will make use of a novel technology termed extracellular flux (XF) analysis that we have adapted for studying Mtb bioenergetics in real time. This technology will be complemented by 13C stable isotope analyses using liquid chromatography mass spectrometry This contribution is significant, because it has the potential to identify a new paradigm that will lead to a detailed mechanistic understanding of how the Mtb ETC communicates with central carbon catabolism, and how disruption of this process could be exploited to sterilize Mtb. This proposal is innovative in our opinion, because the newly adapted technology that is supported by metabolomics, distinguish itself from conventional approaches for studying energy metabolism in pathogenic microbes.

由病原结核分枝杆菌（Mtb）引起的结核病是导致死亡的主要原因

项目成果

Bedaquiline reprograms central metabolism to reveal glycolytic vulnerability in Mycobacterium tuberculosis.

• DOI: 10.1038/s41467-020-19959-4
• 发表时间: 2020-11-30
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Mackenzie JS;Lamprecht DA;Asmal R;Adamson JH;Borah K;Beste DJV;Lee BS;Pethe K;Rousseau S;Krieger I;Sacchettini JC;Glasgow JN;Steyn AJC
• 通讯作者: Steyn AJC

Host Bioenergetic Parameters Reveal Cytotoxicity of Antituberculosis Drugs Undetected Using Conventional Viability Assays.

• DOI: 10.1128/aac.00932-21
• 发表时间: 2021-09-17
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Cumming BM;Baig Z;Addicott KW;Chen D;Steyn AJC
• 通讯作者: Steyn AJC

Relevance of the Warburg Effect in Tuberculosis for Host-Directed Therapy.

• DOI: 10.3389/fcimb.2020.576596
• 发表时间: 2020
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Cumming BM;Pacl HT;Steyn AJC
• 通讯作者: Steyn AJC

Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis.

• DOI: 10.15252/emmm.202013207
• 发表时间: 2021-01-11
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Lee BS;Hards K;Engelhart CA;Hasenoehrl EJ;Kalia NP;Mackenzie JS;Sviriaeva E;Chong SMS;Manimekalai MSS;Koh VH;Chan J;Xu J;Alonso S;Miller MJ;Steyn AJC;Grüber G;Schnappinger D;Berney M;Cook GM;Moraski GC;Pethe K
• 通讯作者: Pethe K