Evaluation of Novel Meliodosis Therapeutics

摘要 类鼻疽伯克霍尔德菌是类鼻疽病的病原体。这种疾病是世界热带和亚热带地区的地方病，但现在被认为是一种新出现的疾病，也是一种具有生物防御重要性的疾病。因为B。由于假鼻疽对许多抗生素具有内在的耐药性，类鼻疽病的治疗是困难的，并且由于细菌变得潜伏的趋势，必须持续延长的时间段。可用于类鼻疽治疗的抗生素谱有限， 在流行地区出现的耐药菌株要求开发新的治疗方法。此外，如果没有新的治疗方法，成功治疗由生物恐怖主义事件引起的感染可能是不可能的，生物恐怖主义事件涉及已经获得额外抗性决定因素的菌株，无论是通过自然手段还是通过恶意基因工程。我们假设几种新的研究药物，其中一些正在进行临床试验，也可能对B有效。假鼻疽为了检验这一假设，将追求两个具体目标。在目标1中，将针对一组>100种临床和环境分离株评估BAL 30072（单内酰胺类抗生素）、头孢霉素（酮内酯类抗生素）和iclaprim（甲氧苄啶类似物）的体外效力，建立工艺中的MIC 90值和每种抗生素的时间-杀灭曲线， 这些分离物的子集。将表达染色体编码的β-内酰胺酶基因，并将其作为潜在的BAL 30072耐药机制进行评价。然后，在目的2中，将在急性B的BALB/c小鼠模型中评估BAL 30072、赛红霉素和iclaprim的体内治疗功效。使用已证实的类鼻疽治疗剂作为对照。由于这些研究药物处于I期至 其他适应症的III期临床试验，证明体外和体内抗B活性。假鼻疽的发现将使这些抗微生物剂能够快速推进到非人灵长类动物的实验和I期临床试验。 公共卫生相关性。密切相关的细菌也会导致难以或不可能治愈的感染，我们相信我们在B方面取得的进展很可能。类鼻疽治疗剂将直接应用于其它生物威胁剂如B的感染。鼻疽和可能出现的病原体B。新洋葱

Abstract Burkholderia pseudomallei is the etiologic agent of melioidosis. This disease is endemic to tropical and subtropical regions of the world but is now considered an emerging disease, as well as a disease of biodefense importance. Because of B. pseudomallei's intrinsic resistance to many antibiotics, melioidosis therapy is difficult and, because of the tendency of the bacterium to become latent, must be continued for extended periods of time. The limited spectrum of antibiotics available for melioidosis treatment, and the emergence of resistant strains in endemic regions calls for development of new therapeutics. Furthermore, successful treatment of infections caused by bioterrorism events involving strains which have acquired additional resistance determinants, whether by natural means or by malicious genetic engineering, may be impossible without new therapeutics. We hypothesize that several new investigational drugs, some of which are in clinical trials, may also be efficacious against B. pseudomallei. Two specific aims will be pursued to test this hypothesis. In Aim 1, in vitro efficacies of BAL30072 (a monobactam), cethromycin (a ketolide) and iclaprim (a trimethoprim analog) will be assessed against a panel of >100 clinical and environmental isolates, establishing MIC90 values in the process and time-kill curves for each antibiotic for a subset of these isolates. Chromosomally encoded p-lactamase genes will be expressed and evaluated as potential BAL30072 resistance mechanisms. In aim 2, then, in vivo therapeutic efficacy of BAL30072, cethromycin and iclaprim will be assessed in a BALB/c mouse model of acute B. pseudomallei infection using proven melioidosis therapeutics as controls. As these investigational drugs are in Phase I through Phase III clinical trials for other indications, demonstration of in vitro and in vivo activity against B. pseudomallei will enable rapid advancement of these antimicrobials to experiments with non-human primates and into Phase I clinical trials. Public Health relevance. Closely related bacteria also cause difficult or impossible to cure infections and we believe that it is likely that the advances we made with B. pseudomallei therapeutics will be directly applicable to infections by other biothreat agents such as B. mallei and perhaps the emerging pathogen B. Cenocepacia