Combatting natural resistance and persistence in non-TB mycobacterial disease

对抗非结核分枝杆菌疾病的自然耐药性和持久性

• 批准号: 10328930
• 负责人: Thomas Dick
• 金额: $ 90.67万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328930
• 关键词: Address; Antibiotics; Antimycobacterial Agents; Antitubercular Agents; Antitubercular Antibiotics; Bacillus; Bacteria; Biological; Biological Assay; Biology; Cell membrane; Cells; Chemicals; Chemistry; Clarithromycin; Clinical; Clinical Trials; Collection; Couples; Cystic Fibrosis; Data; Development; Disease; Drug Kinetics; Drug Tolerance; Elderly; Environment; Funding; Generations; Granuloma; Hemolysis; Incidence; Infection; Knowledge; Lead; Lesion; Libraries; Linezolid; Lung diseases; Lung infections; Macrolides; Medicine; Membrane; Methyltransferase; Microbial Biofilms; Molecular Weight; Multidrug-Resistant Tuberculosis; Mutation; Mycobacterium Infections; Mycobacterium abscessus; Mycobacterium avium; Mycobacterium tuberculosis; Natural Resistance; Nature; Nonprofit Organizations; Organ Transplantation; Oxazolidinones; Patients; Penetrance; Persons; Pharmaceutical Preparations; Pharmacology; Predisposition; Privatization; Property; Pulmonary Tuberculosis; Research Personnel; Resistance; Resistance development; Resources; Ribosomal RNA; Series; Sputum; Structure; Structure-Activity Relationship; Synthesis Chemistry; Testing; Transplant Recipients; Tube; Tuberculosis; Vertebral column; Vulnerable Populations; Work; analog; base; cell envelope; chemical genetics; clinically relevant; cytotoxicity; design; drug candidate; drug discovery; drug standard; experience; genetic approach; genetic resistance; high throughput screening; improved; in vitro Assay; in vivo; innovation; lead optimization; lung lesion; mouse model; mycobacterial; non-tuberculosis mycobacteria; novel; novel antibiotic class; novel therapeutics; pathogen; pharmacophore; preclinical development; predictive test; programs; screening; therapy duration; tuberculosis drugs

Whereas tuberculosis (TB) lung disease, caused by Mycobacterium tuberculosis is decreasing, lung disease due to a group of close relatives of the tubercle bacillus called `Non-Tuberculous Mycobacteria' or NTM, is increasing. NTM, including M. abscessus and M. avium, infect vulnerable people, such as cystic fibrosis and organ transplant patients, but also the elderly and even apparently healthy young people. NTM are ubiquitous in the environment and intrinsically resistant against most antibiotics. The few antibiotics that work in the test tube do not work well in patients. Treatments usually take years and do often fail. Thus, there is an urgent need to develop new antibiotics to provide a better cure for NTM patients. Here, two experienced TB drug discovery experts, a microbiologist and a pharmacologist, will work together with chemistry colleagues and apply the knowledge they gained over the past decade in the development of TB antibiotics to the discovery of new NTM drugs. NTM can form, similar to M. tuberculosis, non-replicating `persister' bacteria as well as biofilms. These pathophysiological relevant forms of the bacteria are not killed effectively by standard drugs. Furthermore, NTM, like M. tuberculosis tend to be sequestered in lung lesions, granulomata, that are not reached well by our current medicines. The investigators have developed assays that allow the identification of molecules that can reach those hiding places and kill NTM persisters and biofilms. They will not only make use of knowledge and tests developed for TB drug discovery, but also of collections of anti-TB molecules that were generated over the past years in the context of TB discovery projects. They have shown that many molecules that kill M. tuberculosis are also active against NTM. This strategy allows for the efficient generation of chemical starting material for the development of new NTM antibiotics. Three approaches will be followed: 1. Screen collections of anti-TB molecules to identify new anti-NTM molecules. They will then identify the subset of molecules that not only kill growing NTM cells but also the `persister' and biofilm forms, and penetrate the lung lesions in which the bacteria are hiding. For compounds that show these properties, the target will be determined to enable rational, structure- based chemical optimization of the molecules. 2. Improve existing NTM antibiotics. Several antibiotics, such as Linezolid, have been shown to work against NTM but have poor potency. They will screen collections of chemical derivatives of these suboptimal antibiotics to identify molecules that are more potent. 3. Develop a new type of antibiotic that disrupts cell membrane integrity of NTM. They have developed this novel concept for TB bacteria and showed that these novel membrane-targeting molecules are also active against NTM. All three approaches will deliver novel anti-NTM molecules that we will be tested in a mouse model of NTM infection. Together, this project will deliver a series of new anti-NTM lead compounds with proven tolerability, exposure and tolerability in mouse models and known mechanism of action. These molecules can then be subjected to full lead optimizations campaigns to deliver new drug candidates for NTM lung disease.

而由结核分枝杆菌引起的肺结核(TB)肺部疾病正在减少，肺部疾病 由于结核杆菌的一群近亲被称为非结核分枝杆菌或NTM，是 越来越多。非结核分枝杆菌，包括脓肿分枝杆菌和禽类分枝杆菌，感染易感人群，如囊性纤维化和 器官移植患者，也包括老年人，甚至表面上健康的年轻人。NTM在中国无处不在 对环境和对大多数抗生素具有内在的抵抗力。在试管中有效的为数不多的抗生素 在病人身上不能很好地工作。治疗通常需要数年时间，而且确实经常失败。因此，迫切需要 开发新的抗生素，为NTM患者提供更好的治疗。在这里，两个有经验的结核病药物发现 专家，一名微生物学家和一名药理学家，将与化学同事合作，应用 他们在过去十年中从开发结核病抗生素到发现新的NTM所获得的知识 毒品。与结核分枝杆菌类似，NTM可以形成不复制的“持久”细菌以及生物膜。这些 标准药物不能有效地杀死与病理生理相关的细菌。此外，NTM， 像结核分枝杆菌一样，倾向于隔离在肺部病变中的肉芽肿，目前还不能很好地到达 药物。研究人员已经开发出一种分析方法，可以识别可以到达的分子 那些藏身之处并杀死NTM顽固者和生物膜。他们不仅会利用知识和测试 为结核病药物发现而开发的，也是过去产生的抗结核病分子的集合 在结核病发现项目的背景下进行了数年的研究。他们已经证明，许多杀死结核分枝杆菌的分子 也积极对抗NTM。这一策略允许高效地产生用于 新NTM抗生素的开发。将采取三种方法：1.筛选抗结核药物 分子识别新的抗NTM分子。然后，他们将识别出不仅杀死 生长的NTM细胞还会形成‘持续体’和生物膜，并渗透到肺部病变中的细菌 都躲起来了。对于表现出这些性质的化合物，目标将被确定为能够实现有理的、结构- 基于分子的化学优化。2.改进现有的NTM抗生素。几种抗生素，如 利奈唑胺已被证明对NTM有效，但效力较差。他们将筛选收集到的化学物质 这些不太理想的抗生素的衍生物来识别更有效的分子。(三)发展新型产业。 破坏NTM细胞膜完整性的抗生素。他们为结核病细菌开发了这一新概念 结果表明，这些新型膜靶向分子也具有抗NTM活性。所有这三种方法 将提供新的抗NTM分子，我们将在NTM感染的小鼠模型上进行测试。总而言之，这 该项目将提供一系列新的抗NTM先导化合物，具有已证实的耐受性、暴露和耐受性 在小鼠模型和已知的作用机制中。然后这些分子可以受到全铅的影响。 优化宣传活动，为NTM肺部疾病提供新的候选药物。

项目成果

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus.

• DOI: 10.1128/aac.00669-22
• 发表时间: 2022-09-20
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9

Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria.

• DOI: 10.1021/acs.jmedchem.3c00398
• 发表时间: 2023-06-08
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Malwal, Satish R. R.;Mazurek, Ben;Ko, Jihee;Xie, Pujun;Barnes, Chikako;Varvitsiotis, Christine;Zimmerman, Matthew D. D.;Olatunji, Samir;Lee, Jaeyong;Xie, Min;Sarathy, Jansy;Caffrey, Martin;Strynadka, Natalie C. J.;Dartois, Veronique;Dick, Thomas;Lee, Bom Nae Rin;Russell, David G. G.;Oldfield, Eric
• 通讯作者: Oldfield, Eric

Critical discussion on drug efflux in Mycobacterium tuberculosis.

• DOI: 10.1093/femsre/fuab050
• 发表时间: 2022-02-09
• 期刊: FEMS microbiology reviews
• 影响因子: 11.3
• 作者: Remm S;Earp JC;Dick T;Dartois V;Seeger MA
• 通讯作者: Seeger MA

Oral β-lactam pairs for the treatment of Mycobacterium avium complex pulmonary disease.

口服β-内酰胺对用于治疗鸟分枝杆菌复合型肺部疾病。

• DOI: 10.1093/infdis/jiad591
• 发表时间: 2023
• 期刊: The Journal of infectious diseases
• 作者: Negatu,DerejeA;Shin,SungJae;Kim,Su-Young;Jhun,ByungWoo;Dartois,Véronique;Dick,Thomas
• 通讯作者: Dick,Thomas

Cyclohexyl-griselimycin Is Active against Mycobacterium abscessus in Mice.

• DOI: 10.1128/aac.01400-21
• 发表时间: 2022-01-18
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Aragaw WW;Roubert C;Fontaine E;Lagrange S;Zimmerman MD;Dartois V;Gengenbacher M;Dick T
• 通讯作者: Dick T