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

GmPcides：解除多种革兰氏阳性病原体抗生素耐药性的化合物

• 批准号: 10162829
• 负责人: Michael G. Caparon
• 金额: $ 37.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10162829
• 关键词: 2-hydroxypyridine; Address; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacillus subtilis; Bacteria; Bacterial Infections; Biochemical; Cause of Death; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Clindamycin; Clinical; Clostridium difficile; Collaborations; Communities; Data; Development; Dose; Drug Design; Drug resistance; Environment; Erythromycin; Essential Genes; Evaluation; Expression Library; Family; Fibrinogen; Genes; Genetic; Goals; Gram-Positive Bacteria; Healthcare; Hospitals; Human; In Vitro; Infection; Lead; Methodology; Microbe; Microbial Biofilms; Microbiology; Modeling; Modification; Molecular; Morbidity - disease rate; Multi-Drug Resistance; Mus; Nosocomial Infections; Organic Chemistry; Organism; Pathogenesis; Pathogenicity; Patients; Positioning Attribute; Prevalence; Process; Property; Recording of previous events; Resistance; Respiratory System; Skin; Skin Tissue; Soft Tissue Infections; Solubility; Streptococcus Group B; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; Structure-Activity Relationship; System; Talents; Testing; Tissues; Toxic effect; Translations; Urinary tract; Urinary tract infection; Vancomycin resistant enterococcus; antibiotic resistant infections; bactericide; catheter associated UTI; chemical genetics; combat; density; druggable target; efficacy evaluation; experimental study; fitness; genetic approach; genetic resource; global health emergency; improved; in vitro Model; in vivo; innovation; methicillin resistant Staphylococcus aureus; mouse model; multi-drug resistant pathogen; next generation; novel; overexpression; pathogen; scaffold; soft tissue; standard of care; synergism; therapeutic development; therapeutic target

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. .

项目摘要/摘要： 医院可获得的感染（HAI）已成为医疗保健危机，是死亡的主要原因。 此外，医院设置了一个致命的多药（MDR）生物的储层，200万 患者每年患有HAI，导致100,000人死亡，额外的医疗保健高达45亿美元 费用。因此，由于MDR引起的感染率的越来越多，全球健康紧急情况 HAI病原体。 为了打击这些病原体，我们引入了GMPCIDES，这是一个新型的环融合2-吡啶酮化合物的家族 对革兰氏阳性物种的杀菌性杀菌性，包括所有七个革兰氏阳性 疾病预防控制中心确定为最重要的抗生素耐药性威胁中的物种。这些细菌包括 梭状芽胞杆菌艰难梭菌，万古霉素耐药肠球菌（VRE），耐甲氧西林的金黄色葡萄球菌金黄色葡萄球菌 （MRSA），耐药性肺炎链球菌（肺炎链球菌），耐红霉素的组A 链球菌（链球菌）和抗克林霉素的B组B链球菌（S. agalactiae）。显著地， GMPCIDE对非分裂细菌具有活性，并以亚致死剂量可以解除抵抗力，以抗拒 在HAI感染的鼠模型中，在体外和体内将MDR微生物敏感到抗生素处理 靶向多个正交过程的护理标准抗生素。 GMPCIDES对革兰氏阴 负生存力或对宿主组织的显着毒性。我们的小组通过结合了GMPCIDES 合成化学家Fredrik Almqvist博士的才华与微生物学家DRS。迈克尔·卡帕伦（Michael Caparon）和斯科特·霍尔格伦（Scott Hultgren） 谁建议利用他们对HAI发病机理的理解和前所未有的能力 操纵2-吡啶酮支架的取代基多样性，以解决翻译所必需的问题 GMPCIDES，包括：i）通过结构活性关系优化活动，稳定性和溶解度 （SAR）和结构 - 秘密关系（SPR）研究； ii）使用A的GMPCIDE目标识别 系统级化学遗传方法和该模型可用的综合遗传资源 革兰氏阳性生物芽孢杆菌； iii）优化对生物膜生长的HAI细菌的活性 社区； iv）评估HAI鼠模型中GMPCIDES改善的体内功效 尿路和软组织感染。此处描述的这些实验将导致关键的识别 在革兰氏阳性HAI病原体中高度保守的可药物目标，并将导致发展 新的抗生素比例和抗生素抑制疗法，以应对MDR HAI革兰氏阳性的挑战 病原体。 。