Repurposing auranofin and ebselen for treatment of multidrug resistant pathogens

重新利用金诺芬和依布硒啉治疗多重耐药病原体

• 批准号: 10251428
• 负责人: Mohamed Seleem
• 金额: $ 32.14万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251428
• 关键词: Amebic colitis; Animal Model; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibiotics; Auranofin; Bacterial Drug Resistance; Bacterial Infections; Caspase; Cells; Cessation of life; Characteristics; Clinical; Clinical Treatment; Clinical Trials; Clostridium difficile; Consumption; Data; Development; Diabetic Foot Ulcer; Dose; Drug Kinetics; FDA approved; Genus staphylococcus; Giardiasis; Goals; Grant; Health; Health Care Costs; Human; IL8 gene; Immune response; In Vitro; Infection; Inflammatory; Inflammatory Response; Intestines; Knowledge; Lead; Methods; Microbial Biofilms; Modeling; Multi-Drug Resistance; Mus; New Drug Approvals; Orphan Drugs; Pharmaceutical Preparations; Phase II Clinical Trials; Process; Production; Protease Domain; Public Health; Reproduction spores; Research; Resistance; Risk; Route; Septicemia; Staphylococcus aureus infection; Streptococcus pneumoniae; System; Systemic infection; Testing; Time; Topical application; Toxin; Uncertainty; United States; Vancomycin resistant enterococcus; Virulence Factors; Wound Infection; Wound models; antibiotic resistant infections; antimicrobial; antimicrobial drug; chronic wound; comparative; cost; cytokine; decubitus ulcer; diabetic; drug discovery; drug efficacy; ebselen; effective therapy; efficacy testing; enteric infection; experimental study; gut colonization; healthcare-associated infections; improved; in vitro testing; in vivo; innovation; insight; methicillin resistant Staphylococcus aureus; mortality; mouse model; multi-drug resistant pathogen; nanomolar; novel; novel therapeutics; pathogen; pathogenic bacteria; pressure; prevent; public health relevance; recurrent infection; skin lesion; wound; wound care; wound healing

Abstract Infections caused by Gram-positive pathogens, including Clostridium difficile, are a leading cause of mortality. Three species—methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pneumoniae and vancomycin-resistant enterococcus (VRE)—are responsible annually for at least 84% of deaths due to antibiotic- resistant infections. C. difficile is the most common and costly healthcare-associated infection with an estimated 29,000 deaths annually. Only one new antibiotic, fidaxomicin, has been approved in the last 30 years for treatment of C. difficile infection and recurrence rates are still high for infections involving hypervirulent strains. There is a desperate need for new drugs with improved efficacy. Unlike the costly and time-consuming process of de novo drug discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation. Studies proposed in this application focus on repurposing one non-antimicrobial approved drug, auranofin, and one clinical molecule, ebselen. These two agents possess potent antibacterial activity, in a low nano molar concentration achievable at a clinical range, against multidrug-resistant pathogens, including MRSA, VRE, and C. difficile. We have demonstrated (in vitro and in vivo) that both drugs are superior to drugs of choice and are capable of 1) killing intracellular and persistent MRSA, 2) disrupting adherent staphylococcal biofilms, 3) suppressing key virulence factors including toxin production, 4) reducing excessive host-inflammatory responses associated with these toxins, 5) significantly reducing both the bacterial load and levels of the pro- inflammatory cytokines in MRSA skin lesions, and 6) enhancing wound healing. Both drugs have additional advantageous qualities against C. difficile including; a) potent activity achievable in a clinical range, b) inhibiting toxin production, c) neutralizing C. difficile toxins by inhibiting the cysteine protease domain, d) inhibiting spore formation, e) inhibiting IL-8 release and protecting cells from effect of toxins, f) preventing intestinal colonization of VRE, and were g) superior to drugs of choice in in vitro testing. The fact that auranofin has been granted orphan-drug status from the FDA for treatment of intestinal amebiasis, and is currently in a Phase II clinical trial for treatment of intestinal giardiasis, further validates our approach. Our overall goal in this application is to further validate auranofin and ebselen as potential treatments for superficial, systemic and intestinal infections caused by multidrug-resistant bacterial pathogens and C. difficile. Our findings in MRSA, VRE and C. difficile will be broadly relevant to other pathogens and may offer a safe, effective, and quick supplement to current approaches for treating bacterial infections.

摘要 由革兰氏阳性病原体引起的感染，包括艰难梭菌，是死亡的主要原因。 三种-耐甲氧西林金黄色葡萄球菌(MRSA)、肺炎链球菌和 万古霉素耐药肠球菌(VRE)-每年至少有84%的死亡是由抗生素引起的- 抵抗力感染。艰难梭菌是最常见和最昂贵的与医疗保健相关的感染，据估计 每年有29,000人死亡。在过去的30年里，只有一种新的抗生素，非达索米星被批准用于治疗 艰难梭菌感染的治疗和涉及超强毒力菌株的感染的复发率仍然很高。 人们迫切需要能提高疗效的新药。与昂贵且耗时的过程不同 在新药开发中，药物再利用是一种减少时间、成本和风险的新方法。 药物创新。本申请中提出的研究重点是改变一种非抗菌药批准药物的用途， Auranofin和一种临床分子ebselen。这两种抗菌剂都具有很强的抗菌活性。 在临床范围内可达到的纳米摩尔浓度，对包括MRSA在内的多重耐药病原体， Vre和艰难梭菌。我们已经证明(在体外和体内)这两种药物都优于首选药物。 并能够1)杀死细胞内和持久的MRSA，2)破坏附着的葡萄球菌生物膜， 3)抑制关键的毒力因子，包括毒素的产生；4)减少过度的宿主炎症 与这些毒素相关的反应，5)显著降低细菌负荷和前 MRSA皮肤损伤中的炎性细胞因子，以及6)促进伤口愈合。这两种药物都有额外的 对艰难梭菌的有利性质包括：a)在临床范围内可获得的有效活性，b)抑制 毒素产生，c)通过抑制半胱氨酸蛋白酶结构域中和艰难梭菌毒素，d)抑制孢子 形成，e)抑制IL-8的释放和保护细胞免受毒素的影响，f)防止肠道定植 在体外试验中，VRE和g)优于首选药物。 Auranofin已获得FDA的孤儿药物地位，用于治疗肠道阿米巴病， 目前正在进行治疗肠道贾第鞭毛虫病的第二阶段临床试验，进一步验证了我们的方法。 我们在这项应用中的总体目标是进一步验证Auranofin和ebselen作为潜在的治疗方法 由多重耐药细菌病原体和艰难梭菌引起的浅表、全身和肠道感染。 我们在MRSA、VRE和艰难梭菌中的发现将与其他病原体广泛相关，并可能提供一种安全、 有效、快速地补充了目前治疗细菌感染的方法。