Therapeutic Development of Antimicrobial Biomimetics

抗菌仿生药物的治疗开发

• 批准号: 7226745
• 负责人: RICHARD W SCOTT
• 金额: $ 99.9万
• 依托单位: POLYMEDIX, INC,
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226745
• 关键词: ADME Study; Acute; Affect; Animal Model; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Antimicrobial Resistance; Attention; Back; Bacteria; Bacterial Infections; Biological; Biological Assay; Biomimetics; Bone Marrow; Canis familiaris; Cardiac; Caring; Cell Line; Cells; Chemicals; Chemistry; Clinical; Clinical Research; Clinical Trials; Collection; Data; Derivation procedure; Development; Dose; Drug or chemical Tissue Distribution; Drug resistance; Economics; Electrophysiology (science); End Point; Enterococcus; Enzymes; Equilibrium; Evaluation; Excretory function; Frequencies; Goals; Guanosine Monophosphate; Healthcare; Hospitals; Host Defense; Human; Immunology; In Vitro; Incidence; Infection; Infusion procedures; Injectable; Institute of Medicine (U.S.); Investigational New Drug Application; Kilogram; Knowledge; Lead; Length of Stay; Lymphoma; Mammalian Cell; Measures; Medical; Membrane; Methods; Micronucleus Tests; Modeling; Morbidity - disease rate; Mus; Mutation; Nosocomial Infections; Nosocomial pneumonia; Numbers; Organ; Organism; Organism Strains; Parents; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phenotype; Plague; Pneumonia; Positioning Attribute; Process; Production; Program Development; Property; Proteins; Pseudomonas; Public Health; Qualifying; Radiolabeled; Range; Rattus; Reporting; Research; Research Personnel; Resistance; Resources; Respiratory Tract Infections; Risk; Rodent; Route; Safety; Sampling; Scheme; Selection Criteria; Series; Signal Transduction; Site; Skin; Sodium Chloride; Streptococcus; Structure; System; Testing; Therapeutic; Thigh structure; Tissues; Toxic effect; Toxicokinetics; Toxicology; Urinary tract infection; Work; analog; analytical method; antimicrobial; antimicrobial drug; base; clinically relevant; cost; cytotoxic; day; design; drug development; hemodynamics; human subject; in vivo; insight; membrane model; methicillin resistant Staphylococcus aureus; method development; microbial; mortality; novel; pathogen; pre-clinical; programs; pulmonary function; radiotracer; receptor; respiratory; scale up; small molecule; success

DESCRIPTION (provided by applicant): The incidence of healthcare-acquired infections has increased significantly in recent years and has become an important cause of morbidity and mortality in hospitals in the US and worldwide. The continuing emergence of drug resistance in clinically-important pathogens has now become a global problem and public health threat. In a 2003 Institute of Medicine report, antimicrobial resistance was described as a paramount microbial threat in the 21st Century. It has been estimated that infections caused by drug-resistant organisms double the duration of hospital stays by patients and economic costs for added medical care have been reported to total up to several billion dollars per year in the US. These alarming increases in the emergence of drug-resistant strains and the associated clinical and economic consequences signal the dire need for development of new antimicrobial agents with activity against these organisms. These agents should be novel and attack new targets to evade resistance issues which plague the success of new but structurally-related antibiotics. Furthermore, these agents should exert their antimicrobial activity via mechanisms that bacteria do not effectively resist. The goals of the Phase 2 research plan are to evaluate the suitability of PMX lead candidates in a drug development program leading to human clinical trials for an anti-infective indication. There is substantial information on preclinical in vivo efficacy of the PMX compounds and particular attention will be directed at in vitro screens, acute and repeat dose toxicity studies, safety pharmacology studies and manufacturing to rapidly determine if an IND can be opened to examine safety and tolerability in human subjects. In addition, medicinal chemistry will continue using the base structures of two preferred lead candidates to identify back-up compounds to substitute into the discovery program if problems are encountered with the lead candidates. The projected use for the developed product is as an iv injectable antibiotic to treat hospital-acquired infections.

描述（由申请人提供）：近年来，医疗保健获得性感染的发生率显著增加，已成为美国和全球医院发病率和死亡率的重要原因。临床上重要的病原体中不断出现的耐药性现已成为全球性问题和公共卫生威胁。在2003年的医学研究所报告中，抗菌素耐药性被描述为21世纪世纪最重要的微生物威胁。据估计，由耐药生物体引起的感染使患者住院时间增加一倍，并且据报道，在美国，用于额外医疗护理的经济成本总计高达每年数十亿美元。耐药菌株出现的这些惊人增加以及相关的临床和经济后果表明迫切需要开发对这些生物体具有活性的新抗微生物剂。这些药物应该是新颖的，并攻击新的靶标，以避免困扰新的但结构相关的抗生素成功的耐药性问题。此外，这些试剂应通过细菌不能有效抵抗的机制发挥其抗微生物活性。II期研究计划的目标是评估PMX先导候选药物在药物开发项目中的适用性，该项目将导致抗感染适应症的人体临床试验。关于PMX化合物的临床前体内疗效有大量信息，将特别关注体外筛选、急性和重复给药毒性研究、安全药理学研究和生产，以快速确定是否可以打开IND，以检查人类受试者的安全性和耐受性。此外，药物化学将继续使用两个首选的主要候选人的基本结构，以确定备用化合物，以取代发现计划，如果遇到问题的主要候选人。开发产品的预期用途是作为静脉注射抗生素治疗医院获得性感染。