Therapeutic Development of Antimicrobial Biomimetics

描述(申请人提供)：近年来，医疗保健获得性感染的发病率显著增加，已成为美国和世界各地医院发病率和死亡率的重要原因。临床重要病原体的耐药性不断出现，现已成为一个全球性问题和公共卫生威胁。在2003年医学研究所的一份报告中，抗菌素耐药性被描述为21世纪最大的微生物威胁。据估计，耐药细菌引起的感染使患者的住院时间增加了一倍，据报道，在美国，每年增加医疗保健的经济成本高达数十亿美元。耐药菌株的出现及其相关的临床和经济后果的这些令人震惊的增加表明，迫切需要开发具有抗这些微生物活性的新的抗菌剂。这些药物应该是新的，并攻击新的靶点，以逃避困扰新的但结构相关的抗生素成功的耐药性问题。此外，这些制剂应该通过细菌不能有效抵抗的机制来发挥其抗菌活性。第二阶段研究计划的目标是评估PMX候选药物在药物开发计划中的适宜性，该计划将导致人类临床试验的抗感染适应症。关于PMX化合物的临床前体内疗效有大量信息，将特别关注体外筛查、急性和重复剂量毒性研究、安全药理学研究和制造，以快速确定是否可以打开IND以检查人体的安全性和耐受性。此外，药物化学将继续使用两个首选的领先候选者的碱基结构来识别备用化合物，以便在发现计划中替代使用，如果领先候选者遇到问题。开发的产品预计将作为静脉注射抗生素用于治疗医院获得性感染。

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.