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

项目总结/摘要： 医院获得性感染（HAI）已成为医疗危机，是死亡的主要原因。 此外，医院环境中存在致命的多药耐药（MDR）微生物， 每年有10万人死于HAI，额外的医疗费用高达45亿美元 开销.因此，由于MDR引起的感染的日益普遍，存在全球卫生紧急情况 HAI病原体。 为了对抗这些病原体，我们引入了GmPcides，一种新颖的环稠合2-吡啶酮化合物家族 其对广谱革兰氏阳性菌种具有杀菌作用，包括所有七种革兰氏阳性菌 疾病预防控制中心确定的最重要的抗寄生虫威胁之一的物种。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.肺炎），红霉素耐药A组 链球菌（S.化脓性链球菌）和克林霉素耐药的B族链球菌（S.无乳）。值得注意的是， GmPcides对非分裂细菌有活性，在亚致死剂量下，可以解除耐药性，重新产生耐药性。 在体外和体内在HAI感染的鼠模型中使MDR微生物对抗生素治疗敏感， 针对多个正交过程的标准护理抗生素。GmPcides对革兰氏- 对宿主组织的负活力或显著毒性。我们的团队通过结合 合成化学家Fredrik Almqvist博士与微生物学家Michael Caparon博士和Scott Hultgren博士的才华 他们建议利用他们对HAI发病机制的理解和他们前所未有的能力， 操纵2-吡啶酮骨架的取代基多样性，以解决翻译 GmPcides，包括：i）通过构效关系优化活性、稳定性和溶解性 (SAR)和结构-性质关系（SPR）研究; ii）使用分子生物学方法鉴定GmPcide靶标; 系统水平的化学遗传学方法和可用于模型的综合遗传资源 iii）针对在生物膜中生长的HAI细菌的活性的优化 iv）在HAI鼠模型中评估改进的GmPcides的体内功效 泌尿道和软组织感染。这里描述的这些实验将导致识别关键的 在革兰氏阳性HAI病原体中高度保守的可药用靶标，并将导致 对抗MDR HAI革兰氏阳性菌挑战的新的预防和解除免疫疗法 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. .