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，可引起人类一系列机会性感染。在囊性纤维化、支气管扩张和慢性阻塞性肺病等结构性肺部疾病中，脓肿分枝杆菌可引起慢性肺部疾病。在这些情况下，脓肿分枝杆菌感染往往无法治愈，并伴有肺功能迅速下降。越来越多的临床分离脓肿分枝杆菌对大多数抗生素具有耐药性，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。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，一次只使用一种β-内酰胺治疗单抗感染。我们已经完成的概念验证研究表明，某些β-内酰胺的组合，每次剂量不到单一β-内酰胺的一半，在体外和肺脓肿分枝杆菌感染的小鼠模型中表现出协同杀菌活性。其中一些组合由口服生物可利用的药物组成。在这个建议中，我们将确定双β-内酰胺组合，在体内对脓肿支原体疾病表现出协同作用，并且可以口服治疗以实现稳定的治愈。随后，我们确定了双β-内酰胺对多种脓分枝杆菌菌株具有最高疗效，因为在引起人类疾病的脓分枝杆菌菌株之间存在显着的基因型和表型异质性。

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.