Chemically diverse antimicrobials from silent biosynthetic pathways

来自沉默生物合成途径的化学多样性抗菌剂

• 批准号: 8602807
• 负责人: Robert Henry Cichewicz
• 金额: $ 36.61万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8602807
• 关键词: Acinetobacter baumannii; Address; American; Americas; Anabolism; Anti-Bacterial Agents; Antifungal Agents; Aspergillus; Aspergillus niger; Bacteria; Biological Assay; Biological Factors; Burkholderia cepacia; Candida; Chemicals; Clinic; Complex; Contracts; Data; Development; Distress; Drug Formulations; Drug resistance; Economics; Electrospray Ionization; Engineering; Enterobacteriaceae; Enterococcus faecium; Environment; Epigenetic Process; Evaluation; Exhibits; Failure; Fractionation; Future; Gene Cluster; Genetic Transcription; Goals; Health; Healthcare; Healthcare Systems; Heart; Human; Immunocompromised Host; In Vitro; Incubators; Infection; Infusion procedures; Investigation; Investments; Laboratories; Laboratory culture; Lead; Left; Libraries; Life; Longevity; Mannose; Mass Spectrum Analysis; Medical; Methodology; Methods; Microbe; Microbial Drug Resistance; Modification; Natural Product Drug; Oklahoma; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Positioning Attribute; Preclinical Drug Evaluation; Production; Property; Provider; Pseudomonas aeruginosa; Publishing; Research; Research Design; Resources; Risk; Sampling; Site; Source; Spectrometry, Mass, Electrospray Ionization; Staphylococcus aureus; Structure; Study Section; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Translating; United States National Institutes of Health; Universities; Work; antimicrobial; antimicrobial drug; base; combat; commercialization; cost; design; drug development; drug discovery; epigenome; experience; fungus; innovation; member; microbial; mortality; novel; novel therapeutics; pathogen; pharmacophore; preclinical study; programs; public health relevance; scaffold; small molecule; small molecule libraries; stem; therapeutic development; therapy development; tool

DESCRIPTION (provided by applicant): Healthcare-associated infections (HAIs) pose a tremendous threat to the personal and financial wellbeing of the American people. Over the last decade, there has been a surge in mortality due to HAIs as a result of several compounding factors (e.g., increased levels of drug resistance among microbes, escalating numbers of immunocompromised patients, and a sharp decline in the production of new antimicrobials). Consequently, there is a critical need for the development of new antifungal and antibacterial therapeutics to stem the loss of human life caused by HAIs. Unfortunately, many modern drug screening programs rely on chemically impoverished libraries that severely compromise their respective lead discovery potentials. A major shortcoming for many of these chemical libraries is the significant degree of compound homogeneity and a lack of structural novelty among their component compounds. The objective of this application is to use a chemical-epigenetics methodology to critically examine the unique secondary metabolites that are encoded by silent biosynthetic pathways in fungi as a source of novel antimicrobials. We will test the central hypothesis that the activation of silent natural-product gene clusters in fungi will provide unparalleled access to chemically diverse secondary metabolites, which we will use for procuring new antibacterial and antifungal leads. The rationale for investigating silent biosynthetic pathways for the production of antimicrobials is that secondary metabolites emerging from this source are expected to be structurally and functionally novel; thus these compounds are anticipated to have significant drug development value. Based on our research group's strong preliminary data, three specific aims have been designed to test the central hypothesis: 1) investigate the range of antimicrobial activities emerging from fungi following chemical-epigenetic modification, 2) use bioassay-guided microplate fractionation in tandem with electrospray-ionization time-of-flight mass spectrometry to dereplicate and purify bioactive natural products for testing against a panel of microbial pathogens, and 3) apply a combination of biosystematic and semisynthetic techniques to probe the structure- activity features of two unique groups of antimicrobial leads previously discovered in the PI's laboratory. This research is significant because it capitalizes on an innovative methodology, chemical epigenetics, to access cryptic natural products from fungi. These compounds represent an untapped source of bioactive organic molecules with outstanding therapeutic applications. It is anticipated that these studies will provide an array of chemically unprecedented natural products that will have superb lead development potential as part of future NIH-sponsored studies.

描述（由申请人提供）：与医疗保健相关的感染（HAIS）对美国人民的个人和财务福祉构成了巨大威胁。在过去的十年中，由于几种复合因素（例如，微生物之间的耐药性水平增加，免疫功能低下的患者数量增加，新抗菌药物的产生急剧下降），由于HAI的死亡率激增。因此，迫切需要开发新的抗真菌和抗菌疗法，以阻止Hais造成的人类生命的丧失。不幸的是，许多现代药物筛查计划依赖化学贫穷的图书馆，这些图书馆严重损害了其各自的铅发现潜力。许多这些化学文库的主要缺点是复合均匀性的重要程度，并且其成分化合物之间缺乏结构新颖性。该应用的目的是使用化学景观学方法来批判性地检查由真菌中静音生物合成途径编码的独特二级代谢产物，作为新型抗菌剂的来源。我们将测试中心假设，即真菌中沉默的天然产物基因簇的激活将无与伦比地访问化学多样化的二次代谢物，我们将用于采购新的抗菌和抗真菌铅。研究抗菌剂生产的无声生物合成途径的理由是，从该来源出现的二级代谢产物有望在结构和功能上新颖。因此，预计这些化合物具有显着的药物发育价值。基于我们研究小组的强大初步数据，已经设计了三个特定目的来检验中心假设：1）研究化学景观修饰后真菌从真菌中出现的抗菌活性的范围，2）使用生物测定引导的微型板材料中的微板材料与抗电气化时间验证的限制质量质量质量的验证，并在微生物病原体和3）应用生物系统和半合成技术的组合来探测PI实验室中先前发现的两个独特的抗菌铅的结构 - 活性特征。这项研究很重要，因为它利用了一种创新的方法论，即化学表观遗传学，以获取真菌的神秘天然产品。这些化合物代表了具有出色治疗应用的未开发的生物活性有机分子的来源。可以预料，这些研究将提供一系列化学前所未有的天然产品，这些天然产物将在未来的NIH赞助研究中具有出色的铅开发潜力。

项目成果

Chlorinated polyketide obtained from a Daldinia sp. treated with the epigenetic modifier suberoylanilide hydroxamic acid.

• DOI: 10.1021/np500522z
• 发表时间: 2014-11-26
• 期刊: JOURNAL OF NATURAL PRODUCTS
• 影响因子: 5.1
• 作者: Du, Lin;King, Jarrod B.;Cichewicz, Robert H.
• 通讯作者: Cichewicz, Robert H.

Diarylcyclopentendione metabolite obtained from a Preussia typharum isolate procured using an unconventional cultivation approach.

• DOI: 10.1021/np300473h
• 发表时间: 2012-10-26
• 期刊: Journal of natural products
• 影响因子: 5.1
• 作者: Du L;King JB;Morrow BH;Shen JK;Miller AN;Cichewicz RH
• 通讯作者: Cichewicz RH

Polyketide glycosides from Bionectria ochroleuca inhibit Candida albicans biofilm formation.

• DOI: 10.1021/np500531j
• 发表时间: 2014-10-24
• 期刊: JOURNAL OF NATURAL PRODUCTS
• 影响因子: 5.1
• 作者: Wang, Bin;You, Jianlan;King, Jarrod B.;Cai, Shengxin;Park, Elizabeth;Powell, Douglas R.;Cichewicz, Robert H.
• 通讯作者: Cichewicz, Robert H.

Secondary metabolites produced by fungi derived from a microbial mat encountered in an iron-rich natural spring.

• DOI: 10.1016/j.tetlet.2012.05.156
• 发表时间: 2012-08-08
• 期刊: TETRAHEDRON LETTERS
• 影响因子: 1.8
• 作者: Gerea, Alexandra L.;Branscum, Katie M.;King, Jarrod B.;You, Jianlan;Powell, Douglas R.;Miller, Andrew N.;Spear, John R.;Cichewicz, Robert H.
• 通讯作者: Cichewicz, Robert H.

Epigenome manipulation as a pathway to new natural product scaffolds and their congeners.

• DOI: 10.1039/b920860g
• 发表时间: 2010-01
• 期刊: Natural product reports
• 影响因子: 11.9
• 作者: Cichewicz RH