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

 描述（由申请方提供）：囊性纤维化患者对结核分枝杆菌感染高度敏感。这种病原体在美国约13%的囊性纤维化患者的痰中检测到。对美罗培南和亚胺培南（目前临床使用的两种强效碳青霉烯类药物）耐药的结核分枝杆菌菌株在美国医院中常见。治疗和控制对现有药物有抗药性的感染需要新的抗生素，这些抗生素可以抑制尚未被靶向的酶。该提案的目的是开发一种基于目前未用于治疗脓肿分支杆菌的新型碳青霉烯药物的更有效方案。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，其是该病原体的生长、存活和毒力所需的（Gupta等人，Nature Medicine，2010;埃尔德米利等人，Structure，2012; Schoonmaker，Journal of Bacteriology，2014）。这种酶也存在于分枝杆菌中（Lavollay等人，Journal of Bacteriology，2011）。虽然我们已经报道了这种新的酶活性被美罗培南和亚胺培南抑制（埃尔德米利et al，Structure，2012），但最近我们证实了尚未在临床上使用的新型碳青霉烯类更有效，不仅抑制结核分枝杆菌的生长，而且抑制结核分枝杆菌的生长。因此，该提案旨在将最近发现的酶的基本发现转化为基于新碳青霉烯类的新方案，用于治疗对现有药物具有耐药性的结核分枝杆菌感染。我们的建议是及时的，并解决了需要新的药物与高效力和特异性，以治疗结核分枝杆菌感染的囊性纤维化患者。

 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.