A strategy to treat M. abscessus infections

结核分枝杆菌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。M.然而，在肺结构性疾病如囊性纤维化、支气管扩张和COPD的情况下，支气管扩张菌有时被认为是呼吸道定植菌。肺气肿可导致慢性肺病。此外，免疫功能正常的绝经后白人妇女也容易受到M。尿道感染。在这些情况下，Mab感染通常是不可治愈的，并与肺功能快速下降有关。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。与其他细菌一样，M。细菌需要其肽聚糖（细菌外骨骼）来维持生存。但是，与大多数细菌不同，M. Pestiessus使用两种不同的酶，即L，D-和D，D-转肽酶，用于合成其肽聚糖的最后一步。我们已经生成了初步数据，以证明这两类酶被不同亚类的β-内酰胺抗生素以不同的效力结合和抑制，并表明两种β-内酰胺（每种酶一种特异性）的组合在体外对M.你好本提案的总体目标是利用这些发现来鉴定在杀灭M.体内寄生虫。这些探索性研究的数据将使我们能够确定双重β-内酰胺是否是治疗M的有效策略。你好如果我们对双β-内酰胺体外协同作用的初步观察在体内得到证实（此处提出），我们就有真实的机会开发基于两种β-内酰胺联合治疗M的新治疗方案。尿道感染。

Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacterium that causes a spectrum of opportunistic infections in humans. M. abscessus can sometimes be considered a respiratory colonizer, however, in the setting of structural lung conditions such as cystic fibrosis, bronchiectasis and COPD, M. abscessus can cause chronic pulmonary disease. In addition, immune competent post-menopausal Caucasian women are also vulnerable to M. abscessus infection. In these settings, Mab 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. Like other bacteria, M. abscessus requires its peptidoglycan (bacterial exoskeleton) for viability. But, unlike most bacteria, M. abscessus uses two distinct enzyme classes, namely L,D- and D,D-transpeptidases, for the final step of synthesis of its peptidoglycan. We have generated preliminary data to demonstrate that the two classes of enzymes are bound and inhibited with varying potencies by different sub-classes of β-lactam antibiotics and shown that a combination of two β-lactams, one specific for each enzyme, exhibits synergy in vitro against M. abscessus. The overall objective of this proposal is to leverage these findings to identify combinations of β-lactams that will exhibit synergy in killing M. abscessus in vivo. Data from these exploratory studies will enable us to determine whether dual β-lactam is an effective strategy to treat M. abscessus. If our preliminary observations of in vitro synergy of dual β-lactam is confirmed in vivo (proposed here), we stand a real chance of developing new treatment regimen based on combination of two β-lactams to treat M. abscessus infections.