Oral dual β-lactams to treat pulmonary M. abscessus disease

脓肿分枝杆菌(以前称为脓肿分枝杆菌)是一种快速生长的非结核分枝杆菌，在人类中引起一系列机会性感染。在囊性纤维化、支气管扩张症和慢性阻塞性肺病等结构性肺部疾病的背景下，脓肿分枝杆菌可导致慢性肺部疾病。在这些情况下，脓肿支原体感染通常是无法治愈的，并与肺功能迅速下降有关。越来越多的脓肿分支杆菌临床分离株对大多数抗生素具有耐药性，因此迫切需要有效对抗这些耐药菌株的新的治疗方案。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。在β-内酰胺类药物中，亚胺培南和头孢西丁通常被认为是治疗脓肿支原体感染的药物。然而，今天，一次只有一种β-内酰胺用于治疗单抗感染。我们已经完成了概念验证研究，证明了某些组合的β-内酰胺类药物，每个组合的剂量不到单一β-内酰胺类药物的一半，在体外和肺部脓肿杆菌感染的小鼠模型中显示出协同杀菌活性。其中一些组合由口服生物利用剂组成。在这项提案中，我们将确定在体内显示出对抗脓肿支原体疾病的协同作用的双β-内酰胺组合，并可以口服达到稳定的治愈。随后，我们确定了双重β-内酰胺类药物对多种脓肿分支杆菌菌株具有最高的疗效，因为在导致人类疾病的脓肿分支杆菌菌株之间存在显著的基因和表型异质性。

Mycobacteroides abscessus (formerly known as Mycobacterium abscessus) is a rapidly growing nontuberculous mycobacterium that causes a spectrum of opportunistic infections in humans. In the setting of structural lung conditions such as cystic fibrosis, bronchiectasis and COPD, M. abscessus can cause chronic pulmonary disease. In these settings, M. abscessus infections are often incurable and associated with rapid lung function decline. A growing number of clinical isolates of M. abscessus are resistant to most antibiotics, therefore, new treatment options that are effective against these drug-resistant strains are desperately needed. 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. Among β-lactams, imipenem and cefoxitin are commonly considered for treating M. abscessus infections. However, today, only a single β-lactam is used at a time to treat Mab infections. We have completed proof-of-concept studies demonstrating that certain combinations of β-lactams, each at less than half the dose for single β-lactams, exhibit synergy in bactericidal activity in vitro and in a mouse model of pulmonary M. abscessus infection. Some of these combinations are comprised of agents that are orally bioavailable. In this proposal, we will identify dual β-lactam combinations that exhibit synergy in vivo against M. abscessus disease and can be administered orally to achieve stable cure. Subsequently, we identify dual β-lactams with highest efficacy against a wide variety of M. abscessus strains as there is significant genotypic and phenotypic heterogeneity among M. abscessus stains that cause disease in humans.