A strategy for new regimens to treat pulmonary Mycobacteroides abscessus infection

在囊性纤维化、支气管扩张和慢性阻塞性肺病等结构性肺病的情况下，非结核性脓肿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，而这些抗生素的疗效很差，而且毒性很大。由于广泛的天然和获得性抗生素耐药性，脓肿分枝杆菌已被指定为“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，迫切需要能够有效对抗这些耐药菌株的新治疗方案。β-内酰胺类抗生素是全球用于治疗人类细菌感染最广泛的一类抗生素，具有良好的安全性和耐受性。然而，今天，一次只使用一种β-内酰胺治疗脓肿分枝杆菌感染。这一建议是基于一个现已被揭穿的历史概念，即所有β-内酰胺具有相同的单一靶点（dd -转肽酶），因此在一个方案中包含多个β-内酰胺将是多余的。我们已经完成了概念验证研究，证明某些β-内酰胺的配对组合，每个剂量不到单个β-内酰胺所需剂量的一半，在体外对脓分枝杆菌的杀菌活性中表现出协同作用，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，我们基于人类感染的自然途径建立了肺脓肿支原体疾病小鼠模型，并观察到体外观察到的β-内酰胺对脓肿支原体的协同作用在该临床前模型中也得以保留。在体外协同作用评估中确定的三种组合由口服β-内酰胺组成。这一发现提出了选择两种口服β-内酰胺的组合可能有效治疗脓肿分枝杆菌疾病的可能性。在这里，我们将通过评估由选择的两种β-内酰胺（可能包括一种额外的口服传统抗生素）组成的新型口服方案是否会对感染脓肿分枝杆菌的小鼠产生稳定的治疗来验证这一假设。实验方案将在C3HeB/FeJ肺脓肿支原体疾病小鼠模型中针对一系列近期临床分离的脓肿支原体复合体进行测试。除了方案的效力外，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.