Mechanism of bukholderia pseudomallei drug tolerance

由革兰氏阴性菌类鼻疽伯克霍尔德氏菌引起的类鼻疽对 大多数抗生素。即使在体外使用相对有效的抗菌药物治疗数月后， 6 - 20%的个体患有复发性B。假鼻疽感染，这表明， 病原体改变其抗菌敏感性的模式，以响应在宿主中遇到的线索。数据 在我们的申请中提出的已经确定亚硝化应激和厌氧作为两种宿主条件， 提升B。类鼻疽耐药性我们的目标是确定抗菌药物， 治疗类鼻疽有效性和鉴定新的药物靶点。我们假设一氧化氮 氧化物和低氧张力驱动B。假鼻疽进入改变的代谢和耐药状态。到 为了解决这一假设，我们将确定：1）介导B抗性的分子适应。 假鼻疽对亚硝化应激的适应机制; 2）促进B厌氧存活的适应机制。 3）亚硝化应激和厌氧停滞对抗菌耐受的贡献。我们 最近开发的细菌学技术，遗传学，微阵列转录谱，细胞培养 系统和生化分析将帮助我们确定适应性和代谢途径， 宽容8与用于患有类鼻疽的人的抗菌剂的比例。合作 与科罗拉多州立大学的史蒂文·道博士一起，我们将确定反硝化防御和 代谢网络有助于8的发病机制。在类鼻疽的鼠模型中的假鼻疽。在 此外，我们将继续努力，以确定抗菌药物有效地防止无呼吸8。 假鼻疽为了实现这一目标，我们已经确定，针对厌氧菌的药物是非常有效的。 有效对抗无呼吸8.而杀死需氧细菌的药物无效。治疗 厌氧抗菌药物对无呼吸8.将在鼠模型中研究类鼻疽 慢性类鼻疽这些研究在RMRCE的范围内，以发现新型抗菌药物 目标和开发抗菌药物，提高对广泛的临床抗生素的疗效 类鼻疽的抵抗力。我们的研究与Schweizer博士在1999年提出的研究协同作用。 项目RP 2.1研究自然抗性8。在需氧条件下对抗菌药物的耐药性试验 急性感染的鼠模型中的条件

Melioidosis caused by the gram-negative bacterium Burkholderia pseudomallei is remarkably resistant to most classes of antibiotics. Even after months of treatment with antibacterials relatively effective in vitro, between 6 and 20% of individuals suffer from relapsed B. pseudomallei infections, indicating that this pathogen alters its patterns of antibacterial susceptibility in response to cues encountered in the host. Data presented in our application have identified nitrosative stress and anaerobiosis as two host conditions that promote B. pseudomallei drug tolerance. Our goal is to identify antibacterials that improve the effectiveness of therapy against melioidosis and identify novel drug targets. We hypothesize that nitric oxide and low oxygen tensions drive B. pseudomallei into an altered metabolic and drug-tolerant state. To address this hypothesis we will determine the: 1) molecular adaptations that mediate resistance of B. pseudomallei to nitrosative stress; 2) adaptive mechanisms that facilitate anaerobic survival of B. pseudomallei; and 3) contribution of nitrosative stress and anaerobic stasis to antibacterial tolerance. Our recently developed bacteriological techniques, genetics, microarray transcriptional profiling, cell culture systems and biochemical assays will help us identify adaptive and metabolic pathways that promote tolerance of 8. pseudomallei to antibacterials used in humans suffering from melioidosis. In collaboration with Dr. Steven Dow at Colorado State University, we will determine how antinitrosative defenses and metabolic networks contribute to the pathogenesis of 8. pseudomallei in a murine model of melioidosis. In addition, we will continue with our efforts to identify antibacterials effective against nonrespiring 8. pseudomallei. Towards this goal, we have already determined that drugs that target anaerobes are very effective against nonrespiring 8. pseudomallei while drugs that kill aerobic bacteria fail. The therapeutic potential of anaerobic antibacterials against nonrespiring 8. pseudomallei will be studied in a murine model of chronic melioidosis. These studies are within the scope of the RMRCE to discover novel antibacterial targets and to develop antibacterials that improve efficacy against the widespread clinical antibiotic resistance of melioidosis. Our investigations synergize with the research proposed by Dr. Schweizer in project RP 2.1 to study the natural resistance of 8. pseudomallei to antibacterials tested under aerobic conditions in a murine model of acute infection