Development of peptide nucleic acid antibiotics

在抗击传染病方面，世界正迅速走向1940年前的S情景。 抗菌素耐药性在全球范围内是一个日益严重的问题，极大地阻碍了我们在世界范围内平息的能力 流感、非典、新冠肺炎、结核病和疟疾等流行病，以及单纯的葡萄球菌 感染。除非开发出创新的策略来生产强大而有效的新类别抗生素， 医疗费用将继续攀升，我们将完全失去与最常见的疾病作斗争的能力 感染。流感和冠状病毒(非典和新冠肺炎)产生了更迫切的目标需求 与肺部感染有关的耐药细菌，如碳青霉烯类耐药肠杆菌科(CRE)，一种常见的 Cre为肺炎克雷伯氏菌(Kp)。疾控中心前主任J·格伯丁最近的一篇文章说 “像CRE这样的超级细菌和其他导致肺部疾病的细菌病原体的风险最大的患者， 是那些已经更容易感染病毒性肺部感染的人，如流感、严重急性肺炎 呼吸综合征(SARS)和新冠肺炎。例如，2009年H1N1流感大流行夺走了近 世界各地有30万条生命。其中许多死亡--29%到55%之间--实际上是由 根据疾控中心的说法，是由继发性细菌性肺炎引起的。最近的一项研究(周，柳叶刀2020,395,1054-1062) 来自武汉的报告称，近50%的新冠肺炎相关死亡病例显示存在继发性细菌 感染(肺炎、败血症、血液感染)。 多药耐药(MDR，对2-3类耐药)、广泛耐药(XDR，对 除粘菌素或替吉环素外的大多数类别)，甚至泛耐药(PDR，对所有类别的耐药性) 近年来，医院内细菌感染激增，并出现了PAN耐药 分离株使这些感染变得越来越难以治疗。像这样的医院获得性感染 高达4%的医院留在美国，而且在致病病原体、抗生素 抵抗力和严重程度。院内感染的一个重要原因是肠杆菌科， 其中包括可以共生或致病的革兰氏阴性杆菌。肠杆菌科有一种 由于它们引起的感染的多样性，造成广泛的临床和经济影响；这个家庭导致许多 肺炎、血流感染(BSI)、尿路感染(UTI)和腹内感染 感染(IAI)。世界卫生组织(WHO)将耐碳青霉烯类肠杆菌科(CRE)列入名单 因为他们的优先病原体名单上迫切需要新的抗生素。因为这些多人的死亡率 耐药感染在30%到50%之间，而且很难找到可行的治疗方法，需要 对于这些病原体的新疗法，必须加以解决。 传染病研究的挑战之一是找到方法来利用日益增长的关于 疾病生物学、转化和进展的潜在机制，以开发新的治疗策略 针对MDR、XDR和PDR细菌感染。以高度保守的RNA序列和结构为目标， 存在于40亿年前的细菌核糖体中，并参与细菌的增殖和生存，是一种 前景看好的方法。核糖体的基本核酸成分rna是药物的有效靶点。 设计，既是治疗的，也是靶子的。我们将针对特定的rRNA单链，它们是保守的 在原核生物中，对翻译启动是必不可少的，但在真核生物中不存在，确保药物靶向 这个序列可以起到广谱治疗的作用。在拟议的工作中，我们将构建序列- 以低聚物为靶标的特定化学修饰的rRNA，可有效地在细胞内传递。短RNA 将被用作使核糖体功能失活的合成分子的靶标，停止 细菌蛋白质合成并导致细菌死亡。NUBAD独特的实验方法和 技术将使我们能够针对以前没有探索过的rRNA组合来研究对细菌的敏感性。 拟议的工作是一项多学科的努力，包括固相有机合成，寡核苷酸 稳定性和传递、RNA靶向筛选、抗菌活性、ADME TOX和体内疗效研究 描述了rRNA序列特异性细胞可渗透结合剂的发展。建议的成功 这项工作将是对目前药物开发中可用的核糖体特异性方法的重大补充。 我们建议使用在原核生物中高度保守的小rRNA靶序列来设计 可以用来抑制微生物的生长，为开发靶向的序列特异性RNA打开了可能性 治疗学。这项工作解决了一个重要的世界卫生问题，即抗菌素耐药性，并提出 采取创造性步骤，寻求解决这个问题的新办法。

The world is rapidly heading towards a pre-1940’s scenario when it comes to fighting infectious disease. Antimicrobial resistance is a growing problem on a global scale, greatly hampering our abilities to quell worldwide epidemics such as influenza, SARS, COVID-19, tuberculosis and malaria, as well as the simple staphylococcus infection. Unless innovative strategies are developed to produce robust and effective new classes of antibiotics, health care costs will continue to climb and we will completely lose our ability to combat even the most common infection. Influenza and coronavirus (SARS and COVID-19) create an even more urgent need for targeting resistant bacteria related to lung infections, such as carbapenem-resistant Enterobacteriaceae (CRE), a common example of CRE being Klebsiella Pneumoniae (KP). Recent article by J. Gerberding, former CDC director states “The patients at greatest risk from superbugs like CRE and other bacterial pathogens that cause lung diseases, are the ones who are already more vulnerable to illness from viral lung infections like influenza, severe acute respiratory syndrome (SARS), and COVID-19. The 2009 H1N1 influenza pandemic, for example, claimed nearly 300,000 lives around the world. Many of those deaths — between 29% and 55% — were actually caused by secondary bacterial pneumonia, according to the CDC.” A recent study (Zhou, Lancet 2020, 395, 1054-1062) from Wuhan reports that almost 50% of COVID-19 related deaths showed evidence of secondary bacterial infections (pneumonia, sepsis, bloodstream infections). Cases of multidrug-resistant (MDR, resistance to 2-3 classes), extensive drug resistance (XDR, resistance to most classes except colistin or tigecycline) and even pan drug resistance (PDR, resistance to all classes) nosocomial bacterial infections have skyrocketed in recent years, and the emergence of pan drug-resistant isolates are making these infections increasingly difficult to treat. Hospital-acquired infections like these account for up to 4% of all hospital stays in the United States and are incredibly diverse in causative pathogen, antibiotic resistance profile, and severity. A significant cause of nosocomial infection is the Enterobacteriaceae family, which includes Gram-negative bacilli that can be commensal or pathogenic. Enterobacteriaceae have a widespread clinical and economic impact due to the diversity of infections they cause; this family causes many infections such as pneumonia, bloodstream infections (BSIs), urinary tract infections (UTIs), and intra-abdominal infections (IAIs). The World Health Organization (WHO) lists carbapenem-resistant Enterobacteriaceae (CRE) as having a critical need for novel antibiotics on their Priority Pathogens list. Because the mortality of these multi drug-resistant infections is between 30 and 50% and there is such difficulty in finding viable treatments, the need for novel therapeutics for these pathogens must be addressed. One of the challenges of research in infectious diseases is to find ways to use the increasing knowledge of the mechanisms underlying disease biology, transformation and progression to develop novel therapeutic strategies targeting MDR, XDR, and PDR bacterial infections. Targeting heavily conserved RNA sequences and structures, present in the 4 billion years old bacterial ribosome, and involved in proliferation and survival of bacteria, is a promising approach. RNA, the essential nucleic acid component of the ribosome, is a validated target for drug design, both as therapeutic and as a target. We will target specific rRNA single strands, which are conserved across prokaryotes, essential for translation initiation but absent in eukaryotes, ensuring that a drug targeting this sequence can function as a broad spectrum therapeutic. In the proposed work, we will construct sequence- specific chemically modified rRNA targeting oligomers that can be effectively delivered inside the cell. Short RNA will be exploited as target for synthetic molecules that inactivate the functioning of the ribosome, stopping bacterial protein synthesis and causing bacterial death. NUBAD’s unique experimental approaches and technologies will allow us to target rRNA combinations not previously explored for susceptibility against bacteria. The work proposed is a multidisciplinary effort encompassing solid-phase organic synthesis, oligonucleotide stability and delivery, RNA targeted screening, antimicrobial activity, ADME TOX, and in vivo efficacy studies describes the development of sequence-specific cell permeable binders of rRNA. The success of the proposed work would be a significant addition to currently available ribosome-specific approaches in drug development. We propose using a small rRNA target sequence, heavily conserved in prokaryotes, to design conjugates that can be employed to inhibit microbial growth, opening possibilities for developing sequence-specific RNA targeted therapeutics. This work addresses an important world health issue, antimicrobial resistance, and presents creative steps towards a novel solution to this problem.