Novel Plague Antibacterials Through Phage Display

说明（申请方提供）：生物战剂与化学武器一样，往往被称为“穷人的原子弹”，因为它们具有破坏潜力，而且相对容易以低成本将其武器化。鼠疫耶尔森氏菌是一种特别令人关注的传染性病原体，因为它已被非常有效地武器化，并导致衰弱和往往致命的疾病-腺鼠疫和肺鼠疫。 虽然存在抗生素治疗来对抗这种药剂的生物攻击，但可用的选择存在严重的缺点。鼠疫菌株已经自然产生，它们对大多数抗生素化合物具有抗药性。对抗鼠疫的抗生素也可以很容易地被基因工程菌株所抵消，这些菌株含有对这些化合物的抗性基因。前苏联的生物武器方案很可能广泛采用了这一做法。因此，保护人民不受可能使用这一制剂的危害，是一个公共卫生和潜在的国家安全问题。一种方法是开发一类新的治疗化合物，用于治疗暴露或患病人群。特别是，开发抑制这种病原体的毒力机制而不是靶向重要过程的药物将代表一类新的抗菌剂，与现有疗法相比具有许多优势。 本申请的总体目标是测试使用噬菌体展示肽技术鉴定削弱鼠疫细菌毒力机制的新型药物的功效。具体而言，我们希望：（1）利用噬菌体展示技术来鉴定与Y菌毒力系统相关的高亲和力肽结合剂。鼠疫杆菌，（2）测试这些肽损害病原体蛋白质的生物化学功能的能力，和（3）使用结构生物学来检查靶标-蛋白质相互作用的性质，以便通过合理设计来改善肽的生物活性。 因此，这些研究旨在作为试点实验，这将导致更广泛的倡议，以检查这些抑制剂在体内的疗效，并将其带入药物开发阶段。生物攻击的威胁要求有各种各样的疗法作为对抗措施。这些研究可能会导致发现新型抗菌化合物，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.