Anti-virulence FimH inhibitors for the treatment and prevention of UTIs

用于治疗和预防尿路感染的抗毒力 FimH 抑制剂

• 批准号: 8645471
• 负责人: Zachary Cusumano
• 金额: $ 30万
• 依托单位: FIMBRION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-18 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645471
• 关键词: Acute; Adherence; Adhesions; Affinity; Antibiotic Prophylaxis; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Attenuated; Bacteria; Bacterial Adhesins; Binding; Bioavailable; Biological Assay; Biological Availability; Bladder; Buffers; Canis familiaris; Cell surface; Cells; Chronic; Clinical; Clostridium difficile; Colitis; Communities; Development; Dose; Drug Design; Drug Kinetics; Epithelial Cells; Epithelium; Escherichia coli; Evaluation; Event; Frequencies; Glycosides; Half-Life; Hemagglutination; High Prevalence; Human; In Vitro; Infection; Infection prevention; Knowledge; Lead; Ligands; Mannose; Mannosides; Measures; Mediating; Medical; Metabolic; Microbial Biofilms; Microbiology; Microsomes; Modeling; Modification; Mus; Oral; Oral Administration; Outcome; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pilum; Plasma; Predisposition; Prevention; Property; Prophylactic treatment; Proteins; Rattus; Recurrence; Resistance; Retreatment; Schedule; Serious Adverse Event; Severities; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Effect; Tissues; Translations; Trimethoprim-Sulfamethoxazole; Urinary tract infection; Urine; Uropathogenic E. coli; Virulence; Virulence Factors; Woman; antimicrobial; bacterial resistance; base; combat; design; effective therapy; efficacy testing; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; interdisciplinary approach; intraperitoneal; killings; lifetime risk; mouse model; new therapeutic target; novel; pre-clinical; pressure; prevent; programs; prophylactic; public health relevance; receptor; resistant strain; response; screening; small molecule; treatment strategy

DESCRIPTION (provided by applicant): Over 15 million women suffer from urinary tract infections (UTI) annually in the U.S. and approximately 20-40% of these patients suffer from multiple recurrences. UTI is unique in its high prevalence of chronic/recurrent infections, which has caused a tremendous need for long-term conventional prophylactic therapy. This is leading to increased antimicrobial resistance of uropathogenic E. coli (UPEC) to first-line empiric therapy such as trimethoprim-sulfamethoxazole (TMP-SMZ). Over the past two decades, elucidation of bacterial pathogenic pathways in UPEC has revealed that the adhesin of type 1 pili, FimH, is an essential virulence factor and thus a novel therapeutic target for the prevention and treatment of UTI. This proposal uses an interdisciplinary approach blending medicinal chemistry, microbiology, and pharmacology to optimize potent, orally available small molecules called mannosides that attenuate acute virulence and recurrent infections by blocking the ability of FimH to bind to mannosylated receptors on bladder epithelial cells. This prevents the adherence to and invasion of UPEC into the bladder epithelium and ultimately prevents the formation of biofilm-like intracellular bacterial communities (IBCs). Further, this prevention of intracellular replication has the potential to mitigate the severity and frequency of recurrence. Rational structure-based ligand design of ¿-D-mannose derivatives has led to the discovery of mannosides with tight FimH binding affinity and can both treat and prevent infection as measured in a murine model of UTI. This proposal is focused on further optimization of mannosides to identify preclinical leads therapeutics. Using knowledge of the structure activity relationships of current mannosides we have elucidated, improved mannosides will be synthesized and assessed in vitro for FimH inhibition and drug-like properties. The in vivo pharmacokinetics of lead mannoside FimH inhibitors will be evaluated in rats and then prioritized compounds in dogs. The most promising compounds will be tested for efficacy in preclinical pharmacodynamic mouse models of UTI. Mice are a relevant model for human UTI and will allow evaluation of in vivo efficacy for prevention/treatment of acute and chronic UTI. Current mannosides generate synergy with TMP-SMZ by excluding UPEC from the bladder epithelium, thus exposing the bacteria to concentrations of TMP-SMZ in the urine sufficient to kill an otherwise clinically resistant strain. The ability of mannoside/TMP-SMZ synergy to treat and prevent chronic/recurrent UTI, and generality to other antimicrobial-resistant strains using optimized inhibitors will be investigated. This proposal is designed to identify innovative, orally bioavailable small molecule therapeutics for the prevention and treatment of UTI. These drugs are also predicted to potentiate the activity of standard antimicrobials for the treatment of UTIs caused by resistant bacteria. Further, results of this proposal promise to serve as a pioneering model and precedent for developing new non-cytotoxic strategies for combating the rise in a myriad of other antibiotic resistant infections.

描述（由申请人提供）：在美国，每年有超过1500万女性患有尿路感染（UTI），这些患者中约20-40%患有多次复发。UTI的独特之处在于其慢性/复发性感染的高患病率，这导致了对长期常规预防性治疗的巨大需求。这导致尿路致病性大肠杆菌的耐药性增加。大肠杆菌（UPEC）的一线经验性治疗，如甲氧苄啶-磺胺甲恶唑（TMP-SMZ）。在过去的二十年中，对UPEC中细菌致病途径的阐明已经揭示了1型皮利粘附素FimH是一种重要的毒力因子，因此是预防UPEC的新的治疗靶点。 治疗UTI。该提案使用跨学科的方法混合药物化学，微生物学和药理学，以优化称为甘露糖苷的有效的口服小分子，通过阻断FimH与膀胱上皮细胞上的甘露糖基化受体结合的能力来减弱急性毒性和复发性感染。这阻止了UPEC粘附和侵入膀胱上皮，并最终阻止了生物膜样细胞内细菌群落（IBC）的形成。此外，这种细胞内复制的预防具有减轻复发的严重程度和频率的潜力。基于配体结构的合理设计-D-甘露糖衍生物导致发现了具有紧密FimH结合亲和力的甘露糖苷，并且可以治疗和预防UTI小鼠模型中测量的感染。该提案的重点是进一步优化甘露糖苷，以确定临床前先导疗法。使用我们已经阐明的当前甘露糖苷的结构活性关系的知识，将合成改进的甘露糖苷并在体外评估FimH抑制和药物样性质。将在大鼠中评价先导甘露糖苷FimH抑制剂的体内药代动力学，然后在犬中优先考虑化合物。将在UTI的临床前药效学小鼠模型中测试最有前途的化合物的功效。小鼠是人UTI的相关模型，并且将允许评价预防/治疗急性和慢性UTI的体内功效。目前的甘露糖苷通过从膀胱上皮排除UPEC而与TMP-SMZ产生协同作用，从而使细菌暴露于尿液中足以杀死另外的临床抗性菌株的浓度的TMP-SMZ。将研究甘露糖苷/TMP-SMZ协同作用治疗和预防慢性/复发性UTI的能力，以及使用优化的抑制剂对其他抗微生物剂耐药菌株的一般性。本建议旨在确定创新，口头 用于预防和治疗UTI的生物可利用的小分子治疗剂。预计这些药物还可增强标准抗微生物剂治疗耐药菌引起的UTI的活性。此外，该提案的结果有望成为开发新的非细胞毒性策略以对抗无数其他抗生素耐药性感染的开创性模型和先例。