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Using Co-culture and Bioinformatics to Discover New Antibiotic Bioactivities

利用共培养和生物信息学发现新的抗生素生物活性

基本信息

批准号：
10056652
负责人：
Elizabeth Anne Shank
金额：
$ 23.02万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2021-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant) There has been a frightening rise in the incidence of disease-causing bacteria resistant to commonly used antibiotics. We therefore urgently need to identify additional molecules to use as antibiotics. Bacteria themselves have historically been the best source for antibiotics and other related 'secondary metabolites'. While the most common and abundant microbial antibiotics have already been harvested as "low-hanging fruit," microbes remain a deep potential source of new secondary metabolites. A critical barrier to obtaining these compounds, however, has been that bacteria rarely produce their full repertoire of secondary metabolites when cultured in the laboratory. What we lack therefore are efficient mechanisms to stimulate the synthesis of these dormant genes required to synthesize these additional, potentially novel, antibiotics. Bacteria grown in co-culture appear to up-regulate their production of secondary metabolites to act as interspecies signaling cues. Our central hypothesis is that co-culture will stimulate the production of molecules not produced in mono-culture, some of which may be previously uncharacterized antibiotics. We will test this hypothesis using the following approaches. In Aim 1 we will use imaging mass spectrometry to broadly detect the production of compounds produced specifically in co-culture, while in Aim 2 we will take a targeted approach and use bioinformatics to identify bacterial strains encoding proteins predicted to create novel secondary metabolites, and use co-culture to stimulate their production. Finally, in Aim 3 we will test the various co-culture-induced metabolites obtained in the previous two aims for antibiotic activity against human pathogens. The most promising leads will be isolated and chemically identified. Our research proposes to exploit microbial co-culture to elicit the production of bacterial metabolites to identify newly discovered antibiotics. Ultimately, the results from this research will contribute to our long-term goal of ensuring that microbes continue to provide us with the building blocks necessary to replenish our arsenal of antibiotics for therapeutic use.

描述（由申请人提供）对常用抗生素产生耐药性的致病细菌的发病率出现了惊人的上升。因此，我们迫切需要确定其他分子用作抗生素。细菌本身在历史上一直是抗生素和其他相关“次级代谢物”的最佳来源。虽然最常见和最丰富的微生物抗生素已经被收获为“低挂水果”，但微生物仍然是新的次级代谢产物的潜在来源。然而，获得这些化合物的一个关键障碍是，在实验室培养时，细菌很少产生完整的次级代谢产物。因此，我们缺乏有效的机制来刺激这些休眠基因的合成，这些休眠基因是合成这些额外的、潜在的新型抗生素所必需的。在共培养物中生长的细菌似乎上调其次级代谢产物的产生，以充当种间信号线索。我们的中心假设是，共培养将刺激产生的分子不产生在单一文化，其中一些可能是以前未知的抗生素。我们将使用以下方法来检验这一假设。在Aim 1中，我们将使用成像质谱法广泛检测共培养中特异性产生的化合物的产生，而在Aim 2中，我们将采取有针对性的方法，并使用生物信息学来识别编码预测产生新型次级代谢产物的蛋白质的细菌菌株，并使用共培养来刺激它们的产生。最后，在目标3中，我们将测试在前两个目标中获得的各种共培养诱导的代谢物对人类病原体的抗生素活性。最有希望的线索将被分离和化学鉴定。我们的研究提出利用微生物共培养来诱导细菌代谢产物的产生，以鉴定新发现的抗生素。最终，这项研究的结果将有助于实现我们的长期目标，即确保微生物继续为我们提供必要的构建模块，以补充我们用于治疗用途的抗生素库。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Natural-Product Antibiotics: Cues for Modulating Bacterial Biofilm Formation.

DOI：
10.1016/j.tim.2017.06.003
发表时间：
2017-12
期刊：
Trends in microbiology
影响因子：
15.9
作者：
Townsley L;Shank EA
通讯作者：
Shank EA

Cyclic di-AMP Acts as an Extracellular Signal That Impacts Bacillus subtilis Biofilm Formation and Plant Attachment.

DOI：
10.1128/mbio.00341-18
发表时间：
2018-03-27
期刊：
mBio
影响因子：
6.4
作者：
Townsley L;Yannarell SM;Huynh TN;Woodward JJ;Shank EA
通讯作者：
Shank EA

Extensive cellular multi-tasking within Bacillus subtilis biofilms.

DOI：
10.1128/msystems.00891-22
发表时间：
2023-08-31
期刊：
mSystems
影响因子：
6.4
作者：
通讯作者：

Large-Scale Bioinformatics Analysis of Bacillus Genomes Uncovers Conserved Roles of Natural Products in Bacterial Physiology.

DOI：
10.1128/msystems.00040-17
发表时间：
2017-11
期刊：
mSystems
影响因子：
6.4
作者：
Grubbs KJ;Bleich RM;Santa Maria KC;Allen SE;Farag S;AgBiome Team;Shank EA;Bowers AA
通讯作者：
Bowers AA

Bacterial Community Members Increase Bacillus subtilis Maintenance on the Roots of Arabidopsis thaliana.