A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection
治疗肺部脓肿分枝杆菌感染的新方案策略
基本信息
- 批准号:10683091
- 负责人:
- 金额:$ 40.94万
- 依托单位:
- 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:2020-09-15 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AbscessAcuteAntibiotic ResistanceAntibiotic TherapyAntibioticsBacteriaBacterial InfectionsBronchiectasisC3HeB/FeJ MouseCase StudyChronicChronic DiseaseChronic Obstructive Pulmonary DiseaseChronic lung diseaseClinicalClinical TrialsCompanionsComplexCystic FibrosisDataDiseaseDisease modelDoseDrug CombinationsDrug resistanceExhibitsFDA approvedGoalsGrowthHumanIn VitroIncidenceIndividualInfectionIntakeKneeLongevityLungLung diseasesLung infectionsMusMycobacterium abscessusMycobacterium tuberculosisNightmareOralOral AdministrationOrganismOutcomePatientsPeptidyltransferasePharmaceutical PreparationsPre-Clinical ModelPredispositionProliferatingRecommendationRegimenResearchResistanceRouteSafetyTestingTimeToxic effectTreatment ProtocolsVirulentWorkantagonistantibiotic designbactericidebeta-Lactamasebeta-Lactamscystic fibrosis patientsefficacy evaluationemerging pathogenexperienceimprovedinhibitormouse modelmutantnovelpreservationpulmonary function declineresistant strainsynergism
项目摘要
In the setting of structural lung conditions such as cystic fibrosis, bronchiectasis and COPD, non-tuberculous bacterium Mycobacteroides abscessus can cause chronic pulmonary disease that is often incurable and associated with rapid lung function decline. Additionally, existing treatment requires more than a year of daily intake of antibiotics with poor efficacies and significant toxicities. M. abscessus has been designated as an “antibiotic nightmare” and “an environmental bacterium turned clinical nightmare” due to extensive natural and acquired antibiotic resistance, which severely limits treatment options. Therefore, there is an urgent unmet need for new treatment options that are effective against these drug-resistant strains. β-lactams are the most widely used class of antibiotics globally to treat bacterial infections in humans and have a demonstrated record of safety and tolerability. However, today, only a single β-lactam is used at a time to treat M. abscessus infections. This recommendation is based on a now debunked historical concept that all β-lactams have the same single target (DD-transpeptidases), thus the inclusion of more than one β- lactam in a regimen would be redundant. We have completed proof-of-concept studies demonstrating that paired combinations of certain β-lactams, each at less than half the dose required for single β-lactams, exhibit synergy in bactericidal activity against M. abscessus in vitro and hypothesized that one agent optimally inhibits LD-transpeptidases while the other targets DD-transpeptidases to achieve synergy. Lastly, we have developed a mouse model of pulmonary M. abscessus disease based on the natural route of infection in humans and observed that synergy between β-lactams against M. abscessus observed in vitro is also preserved in this pre-clinical model. Three of the combinations identified in our in vitro synergy assessment are comprised of orally administered β-lactams. This finding has raised the possibility that a combination of select two oral β-lactams may be effective in treating M. abscessus disease. Here, we will test this hypothesis by assessing whether novel oral regimens consisting of select two β-lactams (which may include an additional oral traditional antibiotic) will produce a stable cure in mice infected with M. abscessus. The experimental regimens will be tested in a C3HeB/FeJ mouse model of pulmonary M. abscessus disease model against a range of recent clinical isolates of the M. abscessus complex. In addition to potency of the regimens, we will also assess their ability to minimize selection of drug-resistance.
在囊性纤维化、支气管扩张和慢性阻塞性肺疾病等结构性肺部疾病的背景下,非结核杆菌脓肿可导致慢性肺部疾病,这种疾病通常是无法治愈的,并与肺功能迅速下降有关。此外,现有的治疗方法需要每天服用一年以上的抗生素,但疗效不佳,毒性很大。由于广泛的天然和获得性抗生素耐药性,脓肿分枝杆菌被指定为“抗生素噩梦”和“环境细菌转变为临床噩梦”,这严重限制了治疗选择。因此,对有效对抗这些耐药菌株的新治疗选择的迫切需求尚未得到满足。β-内酰胺类抗生素是全球使用最广泛的一类抗生素,用于治疗人类的细菌感染,并有证明的安全性和耐受性记录。然而,今天,一次只有一种β-内酰胺用于治疗脓肿支原体感染。这一建议是基于一个现已被揭穿的历史概念,即所有β-内酰胺类药物都有相同的靶点(DD-转肽酶),因此在一个方案中纳入多个β-内酰胺类药物将是多余的。我们已经完成了概念验证研究,证明了某些β-内酰胺类药物的配对组合,每个组合的剂量不到单一β-内酰胺类药物所需剂量的一半,在体外显示出对脓肿支原体的协同杀菌活性,并假设一种药物最佳地抑制LD-转肽酶,而另一种药物靶向DD-转肽酶以实现协同作用。最后,我们基于人类的自然感染途径建立了一种肺脓肿杆菌病的小鼠模型,并观察到在体外观察到的β-内酰胺类药物对脓肿杆菌的协同作用也保存在这个临床前模型中。在我们的体外协同效应评估中确定的三种组合包括口服β-内酰胺类药物。这一发现提出了一种可能性,即选择两种口服β-内酰胺类药物的组合可能对治疗脓肿支原体病有效。在这里,我们将通过评估由精选的两种β-内酰胺类药物(可能包括另一种口服传统抗生素)组成的新型口服方案是否能在感染脓肿分枝杆菌的小鼠中产生稳定的治愈来检验这一假设。实验方案将在C3HeB/FEJ小鼠模型的肺部脓肿分支杆菌病模型中与最近分离的一系列脓肿分支杆菌复合体临床分离株进行比较。除了这些方案的有效性外,我们还将评估它们将选择耐药性降至最低的能力。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Gyanu Lamichhane其他文献
Gyanu Lamichhane的其他文献
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{{ truncateString('Gyanu Lamichhane', 18)}}的其他基金
A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection
治疗肺部脓肿分枝杆菌感染的新方案策略
- 批准号:
10264104 - 财政年份:2020
- 资助金额:
$ 40.94万 - 项目类别:
Oral dual β-lactams to treat pulmonary M. abscessus disease
口服双β-内酰胺治疗肺脓肿分枝杆菌病
- 批准号:
10206006 - 财政年份:2020
- 资助金额:
$ 40.94万 - 项目类别:
Oral dual β-lactams to treat pulmonary M. abscessus disease
口服双β-内酰胺治疗肺脓肿分枝杆菌病
- 批准号:
10027940 - 财政年份:2020
- 资助金额:
$ 40.94万 - 项目类别:
A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection
治疗肺部脓肿分枝杆菌感染的新方案策略
- 批准号:
10458704 - 财政年份:2020
- 资助金额:
$ 40.94万 - 项目类别:
A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection
治疗肺部脓肿分枝杆菌感染的新方案策略
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10096918 - 财政年份:2020
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Towards a new regimen to treat mycobacterial infection in cystic fibrosis patients
寻找治疗囊性纤维化患者分枝杆菌感染的新方案
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