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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

基本信息

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
项目类别：
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

项目摘要

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

项目成果

期刊论文数量（70）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
作者：
通讯作者：

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

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
影响因子：
0
作者：
Negatu,DerejeA;Shin,SungJae;Kim,Su-Young;Jhun,ByungWoo;Dartois,Véronique;Dick,Thomas
通讯作者：
Dick,Thomas

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

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