Exploiting bacterial uptake as a universal platform for antibacterial development

利用细菌摄取作为抗菌开发的通用平台

• 批准号: 9096697
• 负责人: DEBORAH T HUNG
• 金额: $ 24.52万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096697
• 关键词: Acinetobacter; Active Biological Transport; Address; Adenosine; Affinity; Alkynes; Anti-Bacterial Agents; Antibiotics; Bacteria; Binding; Biochemical; Biodistribution; Biological; Biological Assay; Cell Wall; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Cobalamin; Coupled; Cytoplasm; DNA Ligases; Development; Drug Delivery Systems; Drug Efflux; Drug Exposure; Engineering; Enterobacteriaceae; Environment; Enzymes; Extended-spectrum β-lactamase; Fluorescent Dyes; Genes; Genetic; Gram-Negative Bacteria; Health; Healthcare; Housing; Incidence; Industry; Infection; Investments; Klebsiella pneumonia bacterium; Knock-out; Lead; Linezolid; Maps; Measures; Membrane; Minimum Inhibitory Concentration measurement; Modeling; Molecular Profiling; Multi-Drug Resistance; Mus; New Agents; Organism; Pathway interactions; Penetration; Perylene; Pharmaceutical Preparations; Prevalence; Process; Property; Pseudomonas aeruginosa; Reporter; Resistance; Series; Serum; Structure-Activity Relationship; System; Testing; Thigh structure; Toxic effect; Translating; Translational Repression; United States; Vitamin B 12; analog; base; carbapenem-resistant Enterobacteriaceae; drug discovery; efflux pump; extracellular; gene repression; genetic resistance; genome sequencing; genomic profiles; in vivo; inhibitor/antagonist; mortality; mutant; novel; pathogen; prevent; programs; receptor; resistance frequency; resistance mechanism; scaffold; small molecule; uptake; whole genome

 DESCRIPTION (provided by applicant): Multidrug resistant Gram-negative pathogens have been declared a leading, emerging health crisis by the CDC and WHO. Infections with these organisms, including Pseudomonas aeruginosa, Acinetobacter baumanni, and extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae, carry ~60% increased mortality compared to infection with antibiotic-sensitive organism. Alarmingly, the prevalence of infection with resistant forms is steadily climbing, now >20% in some regions of the United States. In this setting, novel antibacterial agents are desperately needed. The most significant hurdle facing novel lead discovery against Gram-negative pathogens is poor drug permeation through the outer membrane, coupled with high rates of drug efflux due to redundant efflux pump systems, as it prevents intracellular drug accumulation and thus whole cell activity. Significant investments in target-based drug discovery efforts have identified many potent leads against conserved bacterial enzyme targets, but low intracellular drug concentrations in Gram-negative pathogens have doomed their development. These challenges in translating potent biochemical potency to effective cellular activity and thus in vivo activity without toxicity have been noted across the industry and uniformly resulted in strategic decisions to abandon this approach, despite the abundance of otherwise promising antibacterial leads. An approach to deliver such drug leads into the bacterial cytoplasm would be transforming, as it would leverage the tremendous investment that has already been made in the optimization of such leads. Further, a general platform for such delivery that could be applied to any such lead would transform the state of the antibiotic pipeline. We suggest that exploitation of native, active bacterial uptake systems is a potentially powerful strategy that can serve as a universal platform to deliver small molecules into the bacterial cytoplasm. By conjugating small molecule antibiotics that are potent for their cognate bacterial enzymatic target to the factor that is imported by these uptake systems, sufficient intracellular concentrations of the antibiotic can be achieved. We propose a novel system founded on the highly conserved and redundant Vitamin B12 uptake systems in P. aeruginosa. These systems efficiently transport cobalamin derivatives from the extracellular environment to the cytoplasm and are capable of transporting a range of cobalamin derivatives. We will develop optimized Vitamin B12-antibacterial conjugates that are programmed for optimal exposure and minimized toxicities from host cell uptake. In addition, we will leverage highly optimized, novel antibacterial drugs and leads whose barrier to development against Gram-negative bacteria is only cytoplasmic delivery as cargos. The successful delivery of this program will not only provide novel Gram-negative antibacterial agents poised for IND-enabling studies, but will also demonstrate the potential of active transport conjugate drug delivery approaches to transform antibacterial drug discovery.

 描述（由适用提供）：疾病预防控制中心和谁宣布了抗多药革兰氏阴性病原体，已宣布为领先的健康危机。与抗生素敏感生物体相比，这些生物体的感染，包括铜绿假单胞菌，铜杆菌和扩展的远光谱β-内酰胺酶（ESBL）肠杆菌科的感染，携带约60％的死亡率。令人震惊的是，以抗性形式感染的流行量正在悄悄攀升，现在在美国某些地区> 20％。在这种情况下，迫切需要新颖的抗菌剂。针对革兰氏阴性病原体的新型铅发现面临的最重要的障碍是通过外膜渗透不良的药物渗透，以及由于冗余外排泵系统而引起的高药物外排，因为它可以防止细胞内药物积累和整个细胞活性。对基于目标的药物发现工作的大量投资已经确定了针对保守的细菌酶靶标的许多潜在铅，但是革兰氏阴性病原体中的细胞内药物浓度较低，已经注定了其发育。在整个行业中，已经注意到了将潜在的生化效力转化为有效细胞活性以及没有毒性的体内活性的这些挑战，并统一地导致了放弃这种方法的战略决策，dospite有望获得丰富的承诺抗菌铅。将这种药物铅输送到细菌细胞质中的一种方法将改变，因为它将利用在优化此类铅进行优化的巨大投资。此外，可以应用于任何此类铅的通用平台将改变抗生素管道的状态。我们建议，对天然活性细菌摄取系统的剥削是一种潜在的强大策略，可以作为通用平台，将小分子输送到细菌细胞质中。通过将可能与这些摄取系统进口的因子相结合的酶靶标的潜在的小分子结合，可以实现足够的细胞内抗生素浓度。我们提出了一个新的系统，该系统建立在铜绿假单胞菌中高度保守和冗余的维生素B12摄取系统上。这些系统有效地将钴胺素衍生物从细胞外环境传输到细胞质，并能够运输一系列钴胺素衍生物。我们将开发优化的维生素B12-抗细菌结合物，这些结合物经过编程，以最佳暴露并最大程度地减少了宿主细胞摄取的毒性。此外，我们将利用高度优化的新型抗菌药物和铅，它们的发育障碍对革兰氏阴性细菌的发育障碍仅仅是细胞质递送，作为嘉戈斯。该程序的成功传递不仅将提供中毒用于辅助研究的新型革兰氏阴性抗菌药物，而且还将证明主动转运共轭药物输送方法的潜力以转化抗菌药物发现。