Target and Non-target Based Resistance to Bedaquiline in South Africa

南非对贝达喹啉的目标和非目标耐药性

• 批准号: 10427170
• 负责人: Ndivhu Makhado
• 金额: $ 34.98万
• 依托单位: SEFAKO MAKGATHO HEALTH SCIENCES UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427170
• 关键词: Alabama; Bacillus; Bioenergetics; Biological Assay; Carbon; Cause of Death; Clinical; Clinical Investigator; Collaborations; Complement; Country; Data; Drug Efflux; Drug Targeting; Drug Tolerance; Drug resistance; Drug resistant Mycobacteria Tuberculosis; Electron Transport; Energy Metabolism; Excretory function; Exhibits; Extreme drug resistant tuberculosis; Frequencies; Genes; Glucose; Goals; Health; Health Sciences; Healthcare; Homeostasis; Incidence; Infectious Agent; Intervention; Knowledge; Link; M. tuberculosis genome; Metabolic; Metabolic stress; Metabolism; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium tuberculosis; Outcome; Oxygen Consumption; Patients; Persons; Pharmaceutical Preparations; Poison; Prevalence; Primary Infection; Process; Regimen; Regulation; Research; Resistance; Respiration; Rifampicin resistance; Role; Science; Series; Shunt Device; South Africa; South African; Succinates; Technology; Testing; Therapeutic; Therapeutic Intervention; Time; Treatment outcome; Tuberculosis; Universities; Variant; Verapamil; base; cohort; drug metabolism; experimental study; extensive drug resistance; extracellular; fitness; flexibility; genome sequencing; glyoxylate; improved; innovation; liquid chromatography mass spectrometry; metabolomics; mortality risk; new technology; novel; pathogenic microbe; preventive intervention; prognostic; programs; prophylactic; stable isotope; transport inhibitor; whole genome

Tuberculosis 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 Mycobacterium tuberculosis (Mtb) strains. In 2015, the South African National Tuberculosis Programme introduced Bedaquiline (BDQ) to strengthen existing regimens for the therapy of rifampicin-resistant TB. This initiative has immediate and far-reaching implications for thousands of South Africans suffering from TB. Concerningly, mutations associated with BDQ resistance (rv0678 and atpE) have been identified in Mtb clones isolated from patients who have never been treated with BDQ or clofazimine (CFZ). Intriguingly, both BDQ and CFZ target the Mtb electron transport chain. These findings, together with the fact that Mtb can persist in a dormant, drug-tolerant state, sometimes reactivating to cause TB decades after the primary infection, indicate an urgent need to better understand the mechanisms of BDQ/CFZ resistance in clinical strains of Mtb. Our long-term goal is to understand the mechanisms of Mtb drug resistance and how this knowledge can be used for prophylactic and therapeutic purposes in South Africa. In this proposal, our central hypothesis is that mutations in rv0678, atpE and elsewhere in the Mtb genome dysregulate central metabolism that contributes to BDQ and CFZ resistance. To test this hypothesis, we have established a global collaborative effort between basic and clinical investigators at Sefako Makgatho Health Sciences University (SMU) in South Africa and the University of Alabama at Birmingham (UAB). As part of this collaboration, we have established a series of specific aims to determine the prevalence of rv0678 and atpE mutations in specific Mtb lineages isolated from patients in South Africa. We will also make use of a novel technology termed extracellular flux (XF96) 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. Lastly, we will further pursue our exciting preliminary findings and determine whether BDQ resistance associated variants contribute to the bacilli's bioenergetic flexibility. This contribution is significant, because it has the potential to identify a new paradigm that will lead to a mechanistic understanding of the emergence of BDQ/CFZ resistance, 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 whole genome sequencing, real-time bioenergetics and metabolomics, distinguishes itself from conventional approaches for studying drug resistance in pathogenic microbes.

结核病是全世界死亡的主要原因。 由于耐药性分枝杆菌（MTB）菌株的蔓延而引起的关注。 2015年，南非 国家结核病计划引入了Bedaquiline（BDQ），以增强现有的治疗方案 利福平耐药的结核病。该计划对成千上万的南方具有直接和深远的影响 非洲人患有结核病。关于，与BDQ抗性相关的突变（RV0678和ATPE）具有 在从未接受过BDQ或Clofazimine（CFZ）治疗的患者中分离的MTB克隆中鉴定出来。 有趣的是，BDQ和CFZ均针对MTB电子传输链。这些发现以及事实 MTB可以持续处于休眠，耐药的状态，有时会重新激活以引起TB数十年后 原发性感染，表明迫切需要更好地了解临床中BDQ/CFZ抗性的机制 MTB菌株。 我们的长期目标是了解MTB耐药性的机制以及这种知识如何 用于南非的预防和治疗目的。在此提议中，我们的中心假设是 RV0678，ATPE和MTB基因组中其他地方的突变失调中心代谢，这有助于 到BDQ和CFZ抗性。为了检验这一假设，我们已经建立了全球合作努力 南非的塞法科·马卡索健康科学大学（SMU）的基础和临床研究人员和 阿拉巴马大学伯明翰大学（UAB）。作为这项合作的一部分，我们建立了一系列 具体目的是确定从从中分离出的特定MTB谱系中RV0678和ATPE突变的患病率 南非的患者。我们还将利用一种称为细胞外通量（XF96）分析的新技术 我们已经适应了实时研究MTB生物能力的。这项技术将由13C补充 使用液相色谱质谱法进行稳定的同位素分析。最后，我们将进一步追求我们的 令人兴奋的初步发现，并确定BDQ抗性是否有助于细菌的变体 生物能灵活性。 这项贡献很重要，因为它有可能确定将导致一个新范式 对BDQ/CFZ抗性出现的机械理解，以及该过程的破坏如何 被利用以对MTB进行消毒。在我们看来，这项建议是创新的，因为新型技术 整个基因组测序，实时生物能学和代谢组学都支持了这一支持，使自己有所区别 从用于研究致病微生物耐药性的常规方法。