GmPcides: Componds that disarm antibiotic resistance in multiple gram-positive pathogens

项目概要/摘要： 医院获得性感染 (HAI) 已成为一场医疗保健危机，也是导致死亡的主要原因。 此外，医院环境中还蕴藏着致命的多重耐药 (MDR) 微生物，达 200 万 每年有患者遭受 HAI，导致 10 万人死亡并带来高达 45 亿美元的额外医疗保健费用 费用。因此，由于 MDR 引起的感染流行率不断上升，出现了全球卫生紧急情况 HAI 病原体。 为了对抗这些病原体，我们引入了 GmPcides，这是一种新型的环稠合 2-吡啶酮化合物家族 对多种革兰氏阳性菌具有杀菌作用，包括所有七种革兰氏阳性菌 疾病预防控制中心确定的物种是最重要的抗生素耐药性威胁之一。这些细菌包括 艰难梭菌、耐万古霉素肠球菌 (VRE)、耐甲氧西林金黄色葡萄球菌 (MRSA)、耐药肺炎链球菌 (S.pneumoniae)、耐红霉素 A 组 链球菌（化脓性链球菌）和克林霉素耐药 B 族链球菌（无乳链球菌）。值得注意的是， GmPcides 对非分裂细菌具有活性，在亚致死剂量下，可以解除耐药性，重新 在 HAI 感染的小鼠模型中，在体外和体内使 MDR 微生物对抗生素治疗敏感，从而 针对多个正交过程的标准护理抗生素。 GmPcides 对革兰氏菌没有影响 负面活力或对宿主组织有显着毒性。我们的小组通过结合以下方法开发了 GmPcides： 合成化学家 Fredrik Almqvist 博士和微生物学家 Drs 的才华。迈克尔·卡帕隆和斯科特·霍特格伦 他们建议利用他们对 HAI 发病机制的了解以及他们前所未有的能力 操纵 2-吡啶酮支架的取代基多样性来解决翻译的重要问题 GmPcides，包括：i) 通过构效关系优化活性、稳定性和溶解度 （SAR）和结构-性能关系（SPR）研究； ii) 使用以下方法识别 GmPcide 目标 系统级化学遗传方法和可用于该模型的综合遗传资源 革兰氏阳性菌枯草芽孢杆菌； iii) 优化针对生物膜中生长的 HAI 细菌的活性 社区； iv) 评估改进的 GmPcides 在 HAI 小鼠模型中的体内功效 尿路和软组织感染。这里描述的这些实验将导致关键的识别 可药物靶标在革兰氏阳性 HAI 病原体中高度保守，将导致 新的抗生素节约疗法和抗生素解除疗法可应对革兰氏阳性耐多药 HAI 的挑战 病原体。 。

PROJECT SUMMARY/ABSTRACT: Hospital-Acquired Infections (HAI) have become a health care crisis and are a leading cause of death. Further the hospital setting harbors a reservoir of lethal multidrug resistant (MDR) organisms, two million patients suffer from HAI annually, resulting in 100,000 deaths and up to $4.5 billion in additional health care expense. Thus, there is a global health emergency due to the growing prevalence of infections caused by MDR HAI pathogens. To combat these pathogens, we introduce GmPcides, a novel family of ring-fused 2-pyridone compounds that are bactericidal against a broad spectrum of Gram-positive species, including all seven Gram-positive species identified by the CDC as among the most significant antibiotic-resistant threats. These bacteria include Clostridioides difficile, vancomycin-resistant Enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), drug-resistant Streptococcus pneumoniae (S. pneumoniae), erythromycin-resistant Group A Streptococcus (S. pyogenes) and clindamycin-resistant Group B Streptococcus (S. agalactiae). Significantly, GmPcides are active against non-dividing bacteria and at sub-lethal doses, can disarm resistance, to re- sensitize MDR microbes to antibiotic treatment, both in vitro and in vivo in a murine model of HAI infection to standard-of-care antibiotics targeting multiple orthogonal processes. GmPcides have no effect on Gram- negative viability or significant toxicity to host tissues. Our group developed GmPcides by combining the talents of synthetic chemist Dr. Fredrik Almqvist with microbiologists Drs. Michael Caparon and Scott Hultgren who propose to take advantage of their understanding of HAI pathogenesis and their unprecedented ability to manipulate the substituent diversity of the 2-pyridone scaffold to address issues essential for the translation of GmPcides, including: i) optimization of activity, stability and solubility through structure-activity relationship (SAR) and structure-property relationship (SPR) studies; ii) Identification of the GmPcide target(s) using a systems-level chemical-genetic approach and the comprehensive genetic resources available for the model Gram-positive organism Bacillus subtilis; iii) optimization of activity against HAI bacteria growing in biofilm communities; and iv) assessment of the in vivo efficacy of improved GmPcides in murine models of HAI urinary tract and soft tissue infection. These experiments described here will lead to the identification of critical druggable target(s) highly conserved among Gram-positive HAI pathogens and will lead to the development of new antibiotic-sparing and antibiotic-disarming therapies to combat the challenge of MDR HAI Gram-positive pathogens. .