Natural Product Derived Inhibitors of ESKAPE Pathogens

ESKAPE 病原体天然产物抑制剂

• 批准号: 10212513
• 负责人: BILL J BAKER
• 金额: $ 65.56万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212513
• 关键词: ADME Study; Accidents; Actinobacteria class; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics; Binding Proteins; Biological; Biological Assay; Blood; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Chemicals; Collection; Cytochrome P450; Cytology; Daptomycin; Databases; Development; Diterpenes; Drug resistance; ESKAPE pathogens; Environment; Evaluation; Future; Goals; Growth; Industry; Infection; Klebsiella pneumoniae; Lead; Libraries; Marine Invertebrates; Maximum Tolerated Dose; Medical; Microbial Biofilms; Miniaturization; Modeling; Mupirocin; National Cancer Institute; Natural Products; Nature; Nevada; Pathway interactions; Permeability; Pharmaceutical Preparations; Phenotype; Plant Sources; Plants; Plasma Proteins; Porifera; Preparation; Property; Reporting; Sampling; Science; Solubility; Source; Superbug; Techniques; Testing; Therapeutic; Toxic effect; Toxin; Water; World Health Organization; antimicrobial; bacterial resistance; bactericide; base; candidate identification; clinically relevant; cytotoxicity; design; drug discovery; efficacy evaluation; endophytic fungi; fungus; high throughput screening; in vivo; in vivo evaluation; inhibitor/antagonist; innovation; insight; marine natural product; microbial; mouse model; novel; pathogen; programs; resistance mechanism; resistant strain; screening; screening program; treatment strategy

The need for new and effective antibiotics is well known, promoted as it is, not just in the annals of science, but in the popular press as well. Resistance mechanisms have rendered many antibiotics ineffective while drug discovery efforts of the industry have turned to more profitable targets. Recently, the CDC reported a death in Nevada caused by a Klebsiella pneumonia strain resistant to all 26 antibiotics in the US arsenal of potential treatments.1 These 'superbugs' remain unusual, however, and the post-antibiotic era is not a foregone conclusion. Properly managed treatment strategies using new antibiotics with novel mechanisms of action hold the promise of antibiotic efficacy well into the future. We propose here a discovery program to identify new antibiotics with the novel mechanisms of action. Our program seeks to discover new antibiotics from natural products, the major source of existing antimicrobial therapeutics. Natural products are an outstanding source of new chemotypes bearing antibiotic properties. Consider that in the 25 years between 1981-2006, 74 new antibiotics were registered as either native natural products, or natural product derivatives, while only 23 totally synthetic compounds were discovered. Indeed, 2 of the 3 new classes of antibiotics discovered since 1970 are natural products (daptomycin and mupirocin). The exquisite selectivity and unimaginable diversity of natural products is no accident; it is designed by nature for survival purposes that are largely driven by microbial warfare. Our discovery pipeline includes a new class of biofilm-selective antibiotics derived from one of our natural product sources, a cold-water sponge. Mechanism-of-action (MOA) studies of these spongian diterpenes in Aim 3 may provide critically needed insights into biofilm disruption. The pipeline also includes high priority antibiotic extracts which we aim to characterize chemically (Aim 1) and biologically (Aim 2) to identify new natural product hits for progression to MOA and related comprehensive advanced biological screening (Aim 3). Further, we aim to keep the pipeline full through primary screening (Aim 2) of new antibiotic screening samples (Aim 1) derived from largely unstudied biological sources, including cold-water marine invertebrates, marine fungi and actinomycetes, and the comprehensive NCI pre-fractionated library of plant and marine natural product extracts. Our project brings innovation in culture miniaturization and elicitation of silent biosynthetic pathways to maximize screening throughput, and a chromatographic technique to reduce effort lost in chemotype re- discovery. All chemodiversity will be evaluated in a high-throughput assay using the clinically relevant ESKAPE pathogens. Hits will be evaluated for cytotoxicity, with those displaying favorable characteristics advancing to comprehensive secondary screening.

对新型有效抗生素的需求是众所周知的，并且不仅在科学史册上得到推广， 但在大众媒体上也是如此。耐药机制使许多抗生素失效，而药物 该行业的发现努力已转向更有利可图的目标。近日，美国疾病控制与预防中心（CDC）报告了一例死亡病例。 内华达州由肺炎克雷伯菌菌株引起，该菌株对美国潜在的所有 26 种抗生素具有耐药性 1 然而，这些“超级细菌”仍然不常见，后抗生素时代尚未结束 结论。使用具有新颖作用机制的新型抗生素进行妥善管理的治疗策略是有效的 抗生素在未来的功效的承诺。我们在这里提出一个发现计划来识别新的 具有新颖作用机制的抗生素。我们的计划旨在从天然物质中发现新的抗生素 产品，现有抗菌疗法的主要来源。天然产品是重要的来源 具有抗生素特性的新化学型。考虑一下，在 1981 年至 2006 年的 25 年间，有 74 个新 抗生素被注册为天然产物或天然产物衍生物，而总共只有23种 发现了合成化合物。事实上，自 1970 年以来发现的 3 类新抗生素中，有 2 类是 天然产物（达托霉素和莫匹罗星）。天然的精妙选择性和难以想象的多样性 产品绝非偶然；它是大自然为生存目的而设计的，而生存目的主要是由微生物战争驱动的。 我们的发现管道包括一类新型生物膜选择性抗生素，源自我们的一种天然抗生素 产品来源，冷水海绵。 Aim 中这些海绵二萜的作用机制 (MOA) 研究 3 可能提供对生物膜破坏至关重要的见解。该管道还包括高优先级抗生素 我们旨在对提取物进行化学（目标 1）和生物学（目标 2）表征，以鉴定新的天然产物 进展为 MOA 和相关的综合高级生物筛查（目标 3）。此外，我们的目标是 通过新抗生素筛选样品（目标 1）的初级筛选（目标 2）保持管道畅通 来自很大程度上未经研究的生物来源，包括冷水海洋无脊椎动物、海洋真菌和 放线菌，以及植物和海洋天然产物提取物的综合 NCI 预分级库。 我们的项目带来了培养小型化和沉默生物合成途径的诱导创新 最大限度地提高筛选通量，并采用色谱技术来减少化学分型重新分析中的工作量损失 发现。所有化学多样性都将使用临床相关的 ESKAPE 在高通量测定中进行评估 病原体。将评估命中的细胞毒性，那些表现出有利特征的将进入 全面的二次筛查。

项目成果

Tuaimenals B-H, Merosesquiterpenes from the Irish Deep-Sea Soft Coral Duva florida with Bioactivity against Cervical Cancer Cell Lines.

Tuaimenals B-H，来自佛罗里达州杜瓦爱尔兰深海软珊瑚的 Merosesquiterpenes，具有抗宫颈癌细胞系的生物活性。

• 发表时间: 2023-01-27
• 影响因子: 5.1
• 作者: Welsch, Joshua T;Smalley, Tracess B;Matlack, Jenet K;Avalon, Nicole E;Binning, Jennifer M;Johnson, Mark P;Allcock, A Louise;Baker, Bill J
• 通讯作者: Baker, Bill J

Tuaimenal A, a Meroterpene from the Irish Deep-Sea Soft Coral Duva florida, Displays Inhibition of the SARS-CoV-2 3CLpro Enzyme.

Tuaimenal A 是一种来自佛罗里达州爱尔兰深海软珊瑚杜瓦的美萜烯，对 SARS-CoV-2 3CLpro 酶具有抑制作用。

• 发表时间: 2022-05-27
• 影响因子: 5.1
• 作者: Avalon, Nicole E;Nafie, Jordan;De Marco Verissimo, Carolina;Warrensford, Luke C;Dietrick, Sarah G;Pittman, Amanda R;Young, Ryan M;Kearns, Fiona L;Smalley, Tracess;Binning, Jennifer M;Dalton, John P;Johnson, Mark P;Woodcock, H Lee;Allcock, A L
• 通讯作者: Allcock, A L

Crannenols A-D, Sesquiterpenoids from the Irish Deep-Sea Soft Coral Acanella arbuscula.

Crannenols A-D，来自爱尔兰深海软珊瑚 Acanella arbuscula 的倍半萜类化合物。

• 发表时间: 2022-10-28
• 影响因子: 5.1
• 作者: Welsch, Joshua T;Young, Ryan M;Allcock, A Louise;Johnson, Mark P;Baker, Bill J
• 通讯作者: Baker, Bill J

Tongalides, Halogenated Butenolides from an Antarctic Delisea sp. Rhodophyte.

Tongalides，来自南极 Delisea sp 的卤化丁烯内酯。

• 发表时间: 2022-07-22
• 影响因子: 5.1
• 作者: Bracegirdle, Joe;Kennedy, Sarah J;Shan, Chuan;Wojtas, Lukasz;Shaw, Lindsey N;Amsler, Charles D;McClintock, James B;Baker, Bill J
• 通讯作者: Baker, Bill J

Neosuberitenone, a New Sesterterpenoid Carbon Skeleton; New Suberitenones; and Bioactivity against Respiratory Syncytial Virus, from the Antarctic Sponge Suberites sp.

Neosuberitenone，一种新的二倍萜碳骨架；

• DOI: 10.3390/md21020107
• 发表时间: 2023-02-01
• 期刊: Marine Drugs
• 影响因子: 5.4
• 作者: J. Bracegirdle;Stine S. H. Olsen;M. Teng;K. Tran;C. Amsler;J. McClintock;B. Baker
• 通讯作者: B. Baker