Optimization of Atypical Antimycobacterial Carbapenem Antibiotics

摘要 分枝杆菌感染，广泛包括结核分枝杆菌(Mtb)，以及由 非结核分枝杆菌(NTM)，如快速生长的脓肿分枝杆菌(Mab)，以及慢速 不断增长的禽分枝杆菌复合体(MAC)代表了一些最具临床挑战性和致命性的 21世纪的传染病。治疗通常包括使用多种抗生素的方案。 时间长了，结果不好是很常见的。-Lactam抗生素传统上不是一种 这些治疗方案中的一部分，由于-内酰胺酶介导的耐药性，以及某些类别的- 内酰胺类药物缺乏抗分枝杆菌活性。值得注意的是，对于肽聚糖交联物，分枝杆菌 主要用一种替代的L，D-转肽酶(LDT)来代替规范的D，D-转肽酶(或 青霉素结合蛋白，后者是通常给药的-内酰胺类药物的主要靶点。LDTS 和ddts是不同源的蛋白质，这在一定程度上解释了这种药物的明显无效。 对分枝杆菌物种的抑制作用。本应用涉及碳青霉烯类抗生素的设计和合成 实质性的和不寻常的(非典型)结构改变，与现有的仅在C2不同的试剂形成对比 位置。此前，我们已经证明了这些支架修饰可以提高对抗Gram的活性- 阴性病原体，最大限度地减少外排，并提高对-内酰胺酶介导的水解的抵抗力。初步 该项目的研究产生了一种非典型的碳青霉烯，与商业上可获得的相比，其效力更高。 碳青霉烯类对不同结核分枝杆菌和单抗临床分离株的抗菌作用。与美罗培南不同，这种新的非典型碳青霉烯 在缺乏-内酰胺酶组合的情况下保持其对耐药分支杆菌病原体的效力 抑制剂，对这些耐药菌株的活性比美罗培南提高20倍。它的 良好的广谱抗分枝杆菌效力(MICs&lt；1g/ml)不会因碳青霉烯酶而减弱 与-内酰胺酶抑制剂联合使用也没有进一步提高分枝杆菌的活性 从而表明-内酰胺酶的稳定性。活性也通过一组不同的非分枝杆菌进行了评估。 表明新抗生素的物种开始显示出对分枝杆菌属的选择性。 其他革兰氏阴性和革兰氏阳性物种。我们现在计划将这一最初的发现发展成口头的 为进一步提高抗分枝杆菌的效力和临床实用价值 这种独特的非典型碳青霉烯的特异性。对碳青霉烯酶的稳定性将是一项口服资产 生物利用剂，因为许多碳青霉烯酶抑制剂(如阿维巴坦)没有口服生物利用度。这个 科学操作由一支高素质的团队指导，包括合成、微生物、生物化学和 结构生物学。一系列彻底和严谨的分析，包括无数的体外和体内PK 评价，将指导发展。

Abstract Mycobacterial infections, broadly including Mycobacterium tuberculosis (Mtb), and those caused by nontuberculous mycobacteria (NTM) like the fast-growing Mycobacterium abscessus (Mab), as well as the slow- growing Mycobacterium avium complex (MAC), represent some of the most clinically challenging and deadly infections of the 21st century. Treatments typically involve regimens of multiple antibiotics that are administered for lengthy periods of time, and poor outcomes are common. -Lactam antibiotics have not traditionally been a part of these treatment regimens, due to -lactamase mediated resistance, and because some classes of - lactams lack antimycobacterial activity. Significantly, for peptidoglycan crosslinking, mycobacterial species primarily use an alternate L,D-transpeptidase (Ldt) in place of the canonical D,D-transpeptidase (Ddt) (or penicillin binding protein, PBP), the latter of which is the primary target of typically administered -lactams. Ldts and Ddts are nonhomologous proteins which, in part, explains the apparent ineffectiveness of this drug class against mycobacterial species. This application involves design and synthesis of carbapenem antibiotics with substantial and unusual (atypical) structural alterations, in contrast to existing agents which differ only at the C2 position. Previously, we have demonstrated that these scaffold modifications can improve activity against Gram- negative pathogens, minimize efflux, and improve resistance to -lactamase-mediated hydrolysis. Preliminary studies for this project yielded an atypical carbapenem with superior potency compared to commercially available carbapenems against diverse Mtb and Mab clinical isolates. Unlike meropenem, this new atypical carbapenem maintained its potency against resistant mycobacterial pathogens in the absence of a combination -lactamase inhibitor, displaying up to 20-fold improvements over meropenem in activity against these resistant strains. Its excellent,broad spectrum antimycobacterial potency (MICs < 1 g/ml) was not diminished by carbapenemase producing mycobacterial species nor was activity further improved by combination with -lactamase inhibitors thus indicating -lactamase stability. Activity was also assessed against a diverse panel of nonmycobacterial species indicating the new antibiotic is beginning to demonstrate selectivity for the mycobacteria genus over other Gram-negative and Gram-positive species. We now plan to develop this initial discovery into an orally bioavailable clinically useful antimycobacterial agent and to further improve the antimycobacterial potency and specificity of this unique atypical carbapenem. Stability to carbapenemases will be an asset in an orally bioavailable agent since many carbapenemase inhibitors (e.g. avibactam) are not orally bioavailable. The scientific operations are guided by a highly qualified team including synthesis, microbiology, biochemistry, and structural biology. A thorough and rigorous array of analyses, including numerous in vitro and in vivo PK evaluations, will guide development.