Novel Antibacterial Scaffold from Natural Products

描述（由申请人提供）：尽管细菌对抗生素的耐药性上升，但新抗生素的开发正在下降。在美国，耐甲氧西林金黄色葡萄球菌感染（MRSA）一直在增加，每年在美国造成19，000人死亡，每年增加30亿至40亿美元的额外医疗保健费用。由于发现或开发的新化学支架相对稀缺，对抗耐药性的问题更加严重。制药公司的大多数抗菌研究都是通过传统的化学驱动的SAR程序开发现有药物的类似物。在过去的几十年里，很少有新的抗生素被引入，大多数抗生素作用于熟悉的靶标。此外，尽管天然产品一直是新抗菌药物的丰富来源，但许多制药公司拥有经过彻底筛选的天然产品库，几乎没有提供多样性或新奇。 人们越来越意识到，天然产物文库，特别是那些真菌来源的文库，需要利用通常在实验室条件下不表达的真菌隐蔽或秘密途径。为了利用蘑菇（担子菌和子囊菌）的大量未被发现的次级代谢产物，LifePharms，Inc.已经建立了一个收集野外收集的，环境挑战的子实体。LifePharms/Microbiotix合作已经鉴定、纯化和表征了两种化合物，它们对革兰氏阳性病原体（包括MSSA、MRSA、MRSE和VRE）表现出有效的抗菌活性（MIC低至0.5 5g/ml），以及良好的细胞毒性特征（CC 50> 100 5g/ml）。这两个先导化合物的化学结构表明它们是新的抗菌化合物。此外，我们已经纯化并部分表征了三种更有效的抗菌化合物，它们将作为替代支架。 在这个I期资助中，我们将i）在一系列测量ADMET的体外试验中评估这些化合物，ii）通过使用半合成方法生成类似物来化学优化这些化合物，以确定结构活性关系并提高效力和选择性，iii）从这些试验获得的数据将为后续类似物的设计提供信息，从而导致类似物设计和评估的迭代过程，以改善支架的功效、选择性和ADMET性质。在第II阶段，将在小鼠中测试符合有效性、选择性和ADMET性质的规定标准的化合物的急性毒性和抗菌有效性。 公共卫生相关性：耐药微生物的抗菌感染是一个日益严重的威胁。LifePharms，Inc.，和Microbiotix，Inc.已经合作发现了结构和机理上新颖的抗菌化合物。这些化合物在体外对几种耐药革兰氏（+）细菌菌株/物种有效。该项目的目标是将这些化合物作为新型抗生素进行临床前开发。

DESCRIPTION (provided by applicant): Despite the rise of bacterial resistance to antibiotics, the development of new antibiotics is on the decline. Methicillin-resistant Staphococcal aureus infections (MRSA) in the United States has been increasing, causing 19,000 deaths per year in the United States and contributing to $3 billion to $4 billion of additional annual health care costs. The issue of combating resistance has been exacerbated by the relative scarcity of new chemical scaffolds discovered or developed. Most of the antibacterial research at pharmaceutical companies has been towards developing analogs of existing drugs through traditional chemistry driven SAR programs. Very few new classes of antibiotics have been introduced in the past decades, and most antibiotics act on familiar targets. In addition, even though natural products have been a rich source of new antibacterials, many pharmaceutical companies have natural product libraries that have been thoroughly screened and offer little in the way of diversity or novelty. There is a growing awareness that natural product libraries, particularly those with a fungal origin, need to exploit fungal cryptic or secret pathways that normally are not expressed in laboratory conditions. To exploit the largely undiscovered secondary metabolites of mushrooms (basidiomycetes and ascomycetes), LifePharms, Inc. has established a collection of field- collected, environmentally challenged fruiting bodies. LifePharms/Microbiotix collaboration has identified, purified, and characterized two compounds that exhibit potent antibacterial activity (MICs as low as 0.5 5g/ml) against Gram-positive pathogens, including MSSA, MRSA, MRSE, and VRE, and favorable cytotoxicity profiles (CC50 > 100 5g/ml). The chemical structures of these two lead compounds indicate they are novel antibacterial compounds. In addition, we have purified and partially characterized three more potent antibacterial compounds that will serve as alternative scaffolds. In this Phase I grant, we will i) evaluate these compounds in a series of in vitro assays that will measure ADMET, ii) chemically optimize these compounds by generating analogs using semi-synthetic methodologies to determine structure activity relationships and to improve potency and selectivity, iii) Data obtained from these assays will inform the design of subsequent analogs, resulting in an iterative process of analog design and evaluation, to improve the efficacy, selectivity, and ADMET properties of the scaffolds. In Phase II, compounds that meet the specified criteria for efficacy, selectivity, and ADMET properties will be tested for acute toxicity and antibacterial efficacy in mice. PUBLIC HEALTH RELEVANCE: Antibacterial infections with drug resistant organisms are a growing threat. LifePharms, Inc., and Microbiotix, Inc. have collaborated to discover structurally and mechanistically novel antibacterial compounds. These compounds are effective against several strains/species of drug resistant Gram (+) bacteria in vitro. The goal of this project is to pursue the preclinical development of these compounds as novel antibiotics.