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

• 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
• 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

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.

摘要

项目成果

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