Towards a new regimen to treat mycobacterial infection in cystic fibrosis patients

 描述(申请人提供)：囊性纤维化患者极易感染脓肿分枝杆菌。在美国，约13%的囊性纤维化患者的痰中检测到这种病原体。脓肿分枝杆菌对美罗培南和亚胺培南具有抗药性，这两种目前正在临床使用的强大碳青霉烯类药物经常在美国医院出现。对现有药物具有抗药性的感染的治疗和控制需要新的抗生素，这种抗生素可以抑制尚未被靶向的酶。这项提议的目的是开发一种更有效的方案，基于目前尚未用于治疗脓肿分枝杆菌的碳青霉烯类新药。我们最近在结核分枝杆菌中发现了一种新的酶，即LD-转肽酶，它是这种病原体生长、生存和毒力所必需的(Gupta等人，自然医学，2010；Erdemli等人，Structure，2012；Schoonaker，细菌学杂志，2014)。这种酶也存在于脓肿分枝杆菌中(Lavollay等人，《细菌学杂志》，2011年)。虽然我们已经报道了美罗培南和亚胺培南抑制这种新的酶活性(Erdemli等人，Structure，2012)，但最近我们证实，尚未投入临床使用的新的碳青霉烯类抗生素更有效，不仅抑制结核分枝杆菌，而且还抑制脓肿分枝杆菌的生长。因此，这项建议旨在将一种新发现的酶的最新基本发现转化为基于新的碳青霉烯类药物的新方案，用于治疗对现有药物具有耐药性的脓肿分枝杆菌感染。我们的建议是及时的，解决了治疗囊性纤维化患者脓肿分枝杆菌感染的高效和特异性新药的需求。

 DESCRIPTION (provided by applicant): Cystic Fibrosis patients are highly susceptible to infections with Mycobacterium abscessus. This pathogen is detected in the sputum of ~13% of cystic fibrosis patients in the US. Mycobacterium abscessus strains that are resistant to meropenem and imipenem, two powerful carbapenem drugs that are currently in clinical use, are routinely seen in US hospitals. Treatment and control of infections that are resistant to existing drugs requires new antibiotics that inhibit enzymes that have not been targeted. The aim of this proposal is to develop a more potent regimen based on new carbapanem drugs that are not currently used for treatment of Mycobacterium abscessus. We recently discovered a novel enzyme, namely LD-transpeptidase, in Mycobacterium tuberculosis that is required for growth, survival and virulence of this pathogen (Gupta et al, Nature Medicine, 2010; Erdemli et al, Structure, 2012; Schoonmaker, Journal of Bacteriology, 2014). This enzyme is also present in Mycobacterium abscessus (Lavollay et al, Journal of Bacteriology, 2011). While we have already reported that this novel enzyme activity is inhibited by meropenem and imipenem (Erdemli et al, Structure, 2012), recently we confirmed that newer carbapenems that are not yet in clinical use are much more potent and inhibit growth of not only Mycobacterium tuberculosis but also Mycobacterium abscessus. Therefore, this proposal aims to translate recent basic findings of a newly discovered enzyme to develop novel regimens based on new carbapenems for treatment of Mycobacterium abscessus infections that are resistant to currently available drugs. Our proposal is timely and addresses the need for new drugs with high potency and specificity to treat Mycobacterium abscessus infections in cystic fibrosis patients.