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

结核分枝杆菌（Mycobacteroides acquisessus）是一种快速生长的非结核分枝杆菌，可引起人类的一系列机会性感染。在结构性肺疾病如囊性纤维化、支气管扩张和COPD的情况下，M.肺气肿可导致慢性肺病。在这种情况下，M。气管感染通常是无法治愈的，并与肺功能迅速下降有关。越来越多的临床分离的M。大肠杆菌对大多数抗生素具有耐药性，因此，迫切需要对这些耐药菌株有效的新治疗方案。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。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M。尿道感染。然而，今天，一次仅使用一种β-内酰胺来治疗Mab感染。我们已经完成了概念验证研究，证明某些β-内酰胺类药物组合（每种药物的剂量均小于单一β-内酰胺类药物的一半）在体外和肺结核小鼠模型中表现出协同杀菌活性。尿道感染。这些组合中的一些由口服生物可利用的药剂组成。在本提案中，我们将鉴定在体内对M表现出协同作用的双重β-内酰胺组合。可口服，达到稳定治愈。随后，我们确定了对多种M具有最高疗效的双重β-内酰胺。由于M.会导致人类疾病的细菌。

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.