Optimization of Atypical Antimycobacterial Carbapenem Antibiotics

摘要 分枝杆菌感染，广泛地包括结核分枝杆菌（Mtb），以及由 非结核分枝杆菌（NTM），如快速生长的结核分枝杆菌（Mab），以及缓慢生长的 生长中的鸟分枝杆菌复合体（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涉及多种抗生素的方案， 结果很差是很常见的。β-内酰胺类抗生素在传统上并不是一种 这些治疗方案的一部分，由于β-内酰胺酶介导的耐药性，并因为某些类别的β-内酰胺酶， 内酰胺缺乏抗分枝杆菌活性。值得注意的是，对于肽聚糖交联，分枝杆菌物种 主要使用替代的L，D-转肽酶（Ldt）代替典型的D，D-转肽酶（Ddt）（或 青霉素结合蛋白，PBP），后者是通常施用的β-内酰胺的主要靶标。LDTs 和Ddts是非同源蛋白质，这部分解释了这类药物明显无效的原因 对抗分枝杆菌该应用涉及碳青霉烯类抗生素的设计和合成， 与仅在C2处不同的现有药物相比， 位置以前，我们已经证明，这些支架修饰可以提高对革兰氏阴性菌的活性。 阴性病原体，最小化外排，并提高对β-内酰胺酶介导的水解的抗性。初步 该项目的研究产生了一种非典型的碳青霉烯，与市售产品相比具有上级效力 碳青霉烯类抗生素对不同的结核分枝杆菌和单克隆抗体临床分离株。与美罗培南不同，这种新型非典型碳青霉烯 在不存在β-内酰胺酶组合的情况下， 抑制剂，在对抗这些耐药菌株的活性方面显示出比美罗培南高20倍的改善。其 碳青霉烯酶不会降低其广谱抗分枝杆菌效力（MIC <1 μ g/ml 与β-内酰胺酶抑制剂组合也不能进一步提高活性 从而表明β-内酰胺酶的稳定性。活性还评估了对一个不同的面板非分枝杆菌 表明新抗生素开始表现出对分枝杆菌属的选择性， 其他革兰氏阴性和革兰氏阳性菌种。我们现在计划将这一初步发现发展成一种口头的 生物可利用的临床有用的抗分枝杆菌剂，并进一步提高抗分枝杆菌效力， 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口服给药的优势。 由于许多碳青霉烯酶抑制剂（例如阿维巴坦）口服不具有生物利用度，因此不得使用生物利用度药物。的 科学操作由一个高素质的团队指导，包括合成，微生物学，生物化学， 结构生物学一系列全面而严格的分析，包括大量体外和体内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.