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

项目摘要/摘要： 医院获得性感染(HAI)已成为一种卫生保健危机，是导致死亡的主要原因。 此外，医院环境中藏有致命的多药耐药(MDR)细菌，200万 患者每年遭受HAI之苦，导致100,000人死亡，高达45亿美元的额外医疗保健 费用。因此，由于MDR引起的感染日益流行，因此出现了全球卫生紧急情况 海里的病原体。 为了对抗这些病原体，我们引入了一种新的环稠合2-吡啶酮化合物家族--GmP 对广泛的革兰氏阳性菌有杀菌作用，包括所有七种革兰氏阳性菌 被美国疾病控制与预防中心确定为最严重的抗生素耐药性威胁的物种。这些细菌包括 艰难梭状芽胞杆菌、耐万古霉素肠球菌、耐甲氧西林金黄色葡萄球菌 耐甲氧西林金黄色葡萄球菌(MRSA)、耐药肺炎链球菌(S肺炎链球菌)、红霉素耐药A组 链球菌(化脓性链球菌)和耐克林霉素B组链球菌(无乳链球菌)。值得注意的是， GmP杀虫剂对不分裂的细菌具有活性，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，在体外和体内使多药耐药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。GmP杀虫剂对Gram- 对宿主组织的存活能力为负或有明显毒性。我们小组通过将GmP与 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-吡啶酮支架的取代基多样性以解决翻译的关键问题 转基因农药，包括：i)通过结构-活性关系优化活性、稳定性和溶解性 (Sar)和结构-性质关系(Spr)研究；ii)使用 系统水平的化学成因方法和可用于该模式的综合遗传资源 革兰氏阳性菌枯草芽孢杆菌；III)生物膜中抗HAI细菌活性的优化 以及iv)改良的转基因杀虫剂在小鼠HAI模型中的体内疗效评估 尿路和软组织感染。这里描述的这些实验将导致识别关键的 可药物靶标(S)在革兰氏阳性HAI病原菌中高度保守，将导致 节省抗生素和解除抗生素武装的新疗法应对耐多药HAI革兰氏阳性的挑战 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. .