A strategy to treat M. abscessus infections

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。脓疡分枝杆菌有时被认为是呼吸道的定植菌，然而，在肺结构性疾病如囊性纤维化、支气管扩张和慢性阻塞性肺病的情况下，脓疡分枝杆菌可引起慢性肺部疾病。此外，免疫功能正常的绝经后高加索妇女也容易感染脓肿分枝杆菌。在这些情况下，单克隆抗体感染往往无法治愈，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。像其他细菌一样，脓疡分枝杆菌需要肽聚糖（细菌外骨骼）来维持生存。但是，与大多数细菌不同的是，脓肿分枝杆菌使用两种不同的酶类，即L，D-转肽酶和D，D-转肽酶，来完成肽聚糖合成的最后一步。我们已经产生了初步的数据来证明这两类酶被不同亚类β-内酰胺抗生素以不同的效力结合和抑制，并表明两种β-内酰胺的组合，每种酶一种特异性，在体外对脓肿分枝杆菌表现出协同作用。本提案的总体目标是利用这些发现来确定β-内酰胺的组合，这些组合将在体内杀死脓肿分枝杆菌中表现出协同作用。这些探索性研究的数据将使我们能够确定双β-内酰胺是否是治疗脓肿分枝杆菌的有效策略。如果我们对双β-内酰胺在体外协同作用的初步观察在体内得到证实（这里提出），我们就有机会开发基于两种β-内酰胺联合治疗脓肿支原体感染的新治疗方案。

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.