Novel Plague Antibacterials Through Phage Display

描述(申请人提供)：生物武器制剂和化学武器一样，常常被称为“穷人的原子弹”，因为它们有可能造成破坏，而且相对容易以较低的成本获得武器装备。鼠疫耶尔森菌是一种特别令人关注的传染病，因为它已经被非常有效地武器化，并导致衰弱的、往往是致命的疾病--腺鼠疫和肺鼠疫。 虽然抗生素治疗可以用来对抗这种制剂的生物攻击，但可用的选择存在严重的缺陷。鼠疫菌株已经自然出现，它们对大多数抗生素化合物都有抗药性。抗击鼠疫的抗生素也可以很容易地被基因工程菌株所对抗，这些菌株对这些化合物具有抗药性基因。这很可能在前苏联的生物武器计划中得到了广泛的追求。因此，保护民众不受可能使用这种制剂的影响是一个公共卫生问题，也是一个潜在的国家安全问题。要做到这一点，一种方法是开发一种新的治疗性化合物，可用于治疗暴露或患病的人群。特别是，开发抑制这种病原体的毒力机制而不是针对重要过程的药物将代表着一类新的抗菌药物，与现有的治疗方法相比具有许多优势。 这项应用的总体目标是测试使用噬菌体展示肽技术来识别破坏鼠疫细菌毒力机制的新药的有效性。具体地说，我们希望：(1)利用噬菌体展示来鉴定鼠疫杆菌毒力系统核心分子的高亲和力多肽结合；(2)测试这些多肽对病原体蛋白质的生化功能的破坏能力；(3)利用结构生物学来研究抑制物-蛋白质相互作用的性质，以便通过合理设计来提高多肽的生物学活性。 因此，这些研究旨在作为一项先导性实验，这将导致更广泛的倡议，以检查这些抑制剂在体内的有效性，并将它们带入药物开发阶段。生物攻击的威胁要求有多种治疗方法作为应对措施。这些研究可能导致发现新型的抗微生物化合物，这可能有助于对抗这些新出现的威胁。

DESCRIPTION (provided by applicant): Biowarfare agents, like chemical weapons, have often been termed the "poor man's atomic bomb," because of their potential for devastation and the relative ease with which they can be weaponized at low cost. Yersinia pestis is an infectious agent of particular concern because it has been very effectively weaponized and causes debilitating and often fatal illnesses -bubonic and pneumonic plague. While antibiotic treatments exist to counter biological attack with this agent, there are serious drawbacks with the available options. Strains of plague have already arisen naturally, which are resistant to most antibiotic compounds. Antibiotics to combat plague can also be countered easily by genetically engineered strains, which harbor resistance genes to these compounds. It is likely that this has been extensively pursued in the former Soviet bioweapons program. It is therefore a matter of public health and potentially national security to protect the population from the possible use of this agent. One way to do this is, to develop a new class of therapeutic compounds that can be used to treat an exposed or ailing population. In particular, developing drugs that inhibit virulence mechanisms of this pathogen instead of targeting vital processes would represent a novel class of antibacterial with many advantages over existing therapies. The overall goal of this application is to test the efficacy of using phage display peptide technologies to identify novel drugs that impair the virulence mechanisms of plague bacterium. Specifically, we wish to: (1) use phage display to identify high affinity peptide binders for molecules central to the virulence system of Y. pestis, (2) test these peptides for their ability to impair biochemical function of the pathogen's proteins and (3) use structural biology to examine the nature of the inhibitor-protein interactions in order to improve by rational design the biological activity of the peptides. These studies are therefore intended as a pilot experiment, which would lead to a broader initiative to examine the efficacy of these inhibitors in vivo, and to bring them to the drug development stage. The threats of biological attack require that a variety of therapies be available as countermeasures. These studies may lead to the discovery of novel classes of antimicrobial compounds, which may serve to combat these emerging threats.