Adjunct therapeutic potential of a repurposed drug inhibiting Mycobacterium abscessus biofilm formation

抑制脓肿分枝杆菌生物膜形成的再利用药物的辅助治疗潜力

基本信息

批准号：
10172839
负责人：
Mary Jackson
金额：
$ 19万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10172839
关键词：
Alveolar wall Animal Model Antibiotic Therapy Antibiotics Antimalarials Artemisinins Bacillus Bacteria Biological Assay Bronchiectasis Cells Chronic Chronic Obstructive Airway Disease Clinic Clinical Colorado Complex Cystic Fibrosis Development Disease Drug Tolerance Drug usage Environment European Extracellular Matrix Genetic Genetic Transcription Genotype Genus Mycobacterium Growth Health Heme Human Hypoxia Immune Evasion Impairment In Vitro Incentives Individual Infection Inflammatory Laboratories Lead Lung Lung Transplantation Lung infections Metabolic Microbial Biofilms Modeling Mus Mycobacterium Infections Mycobacterium abscessus Mycobacterium avium Mycobacterium tuberculosis Nitric Oxide Operative Surgical Procedures Oxides Patients Personal Satisfaction Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphotransferases Physiology Predisposition Prevalence Property Regimen Research Project Grants Route Structure Structure of parenchyma of lung Surgically-Created Resection Cavity Testing Therapeutic Time Tissues Toxic effect Treatment Failure Universities artesunate bactericide chronic infection cystic fibrosis infection cystic fibrosis patients drug repurposing drug standard effective therapy epithelial Na+ channel host colonization improved in vivo inhibitor/antagonist innovation interest lung injury mouse model multidisciplinary mutant new therapeutic target non-tuberculosis mycobacteria pathogen response sensor standard of care success treatment duration

项目摘要

Abstract The prevalence of pulmonary nontuberculous mycobacterial (NTM) infections caused by Mycobacterium abscessus complex (MABSC) species is increasing worldwide and poses a particular threat to susceptible individuals with structural or functional lung conditions such as cystic fibrosis (CF), chronic obstructive pulmonary disease and bronchiectasis. The intrinsic recalcitrance of these pathogens to chemotherapeutic treatments, and alarming treatment failure rates place a high priority on the development of more effective treatment approaches. Although MABSC is known to form microaggregates or biofilms in the thickened alveolar walls, airways and lung cavity of patients, the precise contribution of biofilm formation to MABSC infection and recalcitrance to drug treatment has never been clearly established. Using clinically approved drugs thought to target a key transcriptional regulator (DosRS) required for mycobacteria to enter a state of non-replicating persistence and which we recently found to be potent inhibitors of MABSC biofilm formation, this application proposes to determine, for the first time, whether adding a biofilm inhibitor to standard antibiotic regimens may improve cure. Proof-of-concept of the therapeutic benefit of this approach with clinically-used drugs could be a short route to the clinic. Aim 1 will first test the hypothesis that, through its involvement in inducing a state of persistence in response to hypoxia, the two-component regulator DosRS contributes to the ability of MABSC to form biofilms and develop phenotypic drug tolerance in a chronic CF (b-ENaC-Tg) mouse model of MABSC infection recently developed at Colorado State University. Aim 2 will validate DosRS as the bona fide target of the biofilm inhibitors in MABSC. Finally, Aim 3 will assess the adjunct therapeutic potential of these biofilm inhibitors in MABSC- infected b-ENaC-Tg mice.

抽象的由分枝杆菌引起的肺无结支菌分枝杆菌（NTM）感染的患病率腹肌复合物（MABSC）种类在全球范围内增加，并对易感性构成了特殊的威胁具有结构或功能性肺部条件的个体，例如囊性纤维化（CF），慢性阻塞性肺部疾病和支气管扩张。这些病原体对化学治疗的固有顽固性治疗和令人震惊的治疗失败率将更高的重点放在更有效的发展方面治疗方法。尽管已知MABSC在增厚的肺泡壁，气道和患者的肺腔，生物膜形成对MABSC感染的精确贡献，并重新稳定从未明确确定药物治疗。使用经过临床认可的药物来瞄准钥匙分枝杆菌进入非复制持久性状态需要的转录调节器（DOSR）和我们最近发现它是MABSC生物膜形成的有效抑制剂，该应用建议首次确定将生物膜抑制剂添加到标准抗生素方案中是否可以改善治愈。使用临床药物对这种方法的治疗益处的概念证明可能是很短的通往诊所的途径。 AIM 1将首先检验以下假设，即通过参与诱导持久状态以应对缺氧，两个组分调节剂DOSR有助于MABSC形成生物膜并发展的能力 MABSC感染的慢性CF（B-ENAC-TG）小鼠模型中的表型药物耐受性最近开发了在科罗拉多州立大学。 AIM 2将验证DOSR作为生物膜抑制剂的真正目标 mabsc。最后，AIM 3将评估这些生物膜抑制剂在MABSC-的辅助治疗潜力感染的B-ENAC-TG小鼠。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Therapeutic efficacy of antimalarial drugs targeting DosRS signaling in Mycobacterium abscessus.

DOI：
10.1126/scitranslmed.abj3860
发表时间：
2022-02-23
期刊：
Science translational medicine
影响因子：
17.1
作者：
Belardinelli JM;Verma D;Li W;Avanzi C;Wiersma CJ;Williams JT;Johnson BK;Zimmerman M;Whittel N;Angala B;Wang H;Jones V;Dartois V;de Moura VCN;Gonzalez-Juarrero M;Pearce C;Schenkel AR;Malcolm KC;Nick JA;Charman SA;Wells TNC;Podell BK;Vennerstrom JL;Ordway DJ;Abramovitch RB;Jackson M
通讯作者：
Jackson M

2-Aminoimidazoles Inhibit Mycobacterium abscessus Biofilms in a Zinc-Dependent Manner.

DOI：
10.3390/ijms23062950
发表时间：
2022-03-09
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Belardinelli JM;Li W;Martin KH;Zeiler MJ;Lian E;Avanzi C;Wiersma CJ;Nguyen TV;Angala B;de Moura VCN;Jones V;Borlee BR;Melander C;Jackson M
通讯作者：
Jackson M

Unique Features of Mycobacterium abscessus Biofilms Formed in Synthetic Cystic Fibrosis Medium.

DOI：
10.3389/fmicb.2021.743126
发表时间：
2021
期刊：
Frontiers in microbiology
影响因子：
5.2
作者：
Belardinelli JM;Li W;Avanzi C;Angala SK;Lian E;Wiersma CJ;Palčeková Z;Martin KH;Angala B;de Moura VCN;Kerns C;Jones V;Gonzalez-Juarrero M;Davidson RM;Nick JA;Borlee BR;Jackson M
通讯作者：
Jackson M