A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection

在囊性纤维化、支气管扩张和COPD等结构性肺部疾病的背景下，非结核性细菌结核分枝杆菌可引起慢性肺部疾病，这种疾病通常无法治愈，并与肺功能快速下降相关。此外，现有的治疗方法需要每天服用抗生素一年以上，疗效差，毒性大。M.由于广泛的自然和获得性抗生素耐药性，它已被指定为“抗生素噩梦”和“环境细菌变成临床噩梦”，这严重限制了治疗选择。因此，迫切需要对这些耐药菌株有效的新治疗选择。β-内酰胺类抗生素是全球最广泛使用的一类抗生素，用于治疗人类细菌感染，并且具有已证明的安全性和耐受性记录。然而，今天，一次仅使用单一β-内酰胺来治疗M。尿道感染。该建议基于一个现已被揭穿的历史概念，即所有β-内酰胺类药物都具有相同的单一靶标（DD-转肽酶），因此在治疗方案中纳入一种以上的β-内酰胺类药物是多余的。我们已经完成了概念验证研究，证明某些β-内酰胺的成对组合（每种剂量小于单一β-内酰胺所需剂量的一半）在对M的杀菌活性方面表现出协同作用。在体外进行了研究，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，我们建立了小鼠肺M。基于人的自然感染途径，观察到β-内酰胺类药物对M.在体外观察到的水肿也保留在该临床前模型中。在我们的体外协同作用评估中确定的三种组合由口服给药的β-内酰胺组成。这一发现提出了选择两种口服β-内酰胺类药物联合治疗M的可能性。得了脊髓灰质炎。在此，我们将通过评估由选择的两种β-内酰胺（可能包括额外的口服传统抗生素）组成的新型口服方案是否会在感染M的小鼠中产生稳定的治愈来验证这一假设。你好将在肺M的C3 HeB/FeJ小鼠模型中测试实验方案。针对一系列近期临床分离的M.你有恋母情结除了这些方案的效力外，我们还将评估它们最大限度地减少耐药性选择的能力。

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.