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Genetic basis of metabolite production against clinically-derived pathogens

针对临床衍生病原体的代谢产物产生的遗传基础

基本信息

批准号：
10796488
负责人：
Hans Wildschutte
金额：
$ 9.42万
依托单位：
BOWLING GREEN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-08-31
项目状态：
已结题

项目摘要

Mortality from multi-drug resistant (MDR) bacterial infections is projected to cause 10 million deaths per year worldwide by 2050, making antibiotic resistance a vital threat to society. Fueling this crisis even further is the increased use of antibiotics among 45-97% of COVID-19 patients, which will likely boost selective pressure for MDR phenotypes. Unfortunately, with the misuse and overuse of these chemical compounds, pathogens have evolved several mechanisms to resist all currently used anti-infective agents. The World Health Organization recently deemed carbapenem resistant Pseudomonas aeruginosa as one of the most difficult infections to treat, so future management of this species and other Gram-negative pathogens will require novel, yet undiscovered, antibiotics. As a bacterial group, environemtnal Pseudomonas strains (env-Ps) are well known for their extensive genomic content and diversity. Owed to their genetic complexity is the production of an assorted repertoire of secondary metabolites that have been shown to prevent the growth of pathogenic fungi, breakdown complex recalcitrant compounds, exhibit anti-tumor activity, and inhibit a wide range of bacterial pathogens including methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis. Moreover, soil and freshwater environments are dominated worldwide by pseudomonads, whose global abundance suggest the expression of certain traits that are advantageous to ecological survival. In contrast, P. aeruginosa is observed infrequently in ecological settings. One trait that is likely to contribute to such fitness effects of env-Ps is the ability to antagonize nearby competitors through production of antimicrobial compounds. Previous work showed that water-derived env-Ps were able to inhibit cystic fibrosis (CF) derived pathogens including P. aeruginosa, Burkholderia, Achromobacter, and Stenotrophomonas species, and subsequently identified gene clusters involved in antagonistic activity within the environmental strains. As a continuation of this project, env-Ps from nutrient-rich water systems are hypothesized to be sources of potent antimicrobial activity. Indeed, preliminary data shows that env-Ps from a polluted river exhibited the remarkable ability to inhibit CF-derived extensively drug resistant (XDR) pathogens, including carbapenem resistant P. aeruginosa. In this study, an innovation approach using culturable bacteria will be utilized to link antagonistic activity (phenotype) to diverse biosynthetic gene clusters (genotype) involved in antimicrobial activity. By investigating direct competitive interactions between env-Ps and XDR pathogens, novel antagonistic factors are expected to be identified. This will be achieved by (i) isolating and determining the antimicrobial activity of env-Ps from polluted water columns; (ii) identification of biosynthetic gene clusters involved in the activity; and (iii) initial characterization of encoded undiscovered compounds. Combined results will be used to identify metrics that select for potent antagonistic strains for the future of targeted novel antimicrobial compound discovery.

多药耐药（MDR）细菌感染的死亡率预计每年造成1000万人死亡到2050年，抗生素耐药性将成为对社会的重大威胁。进一步加剧这场危机的是 45-97%的COVID-19患者增加使用抗生素，这可能会增加选择性压力， MDR表型。不幸的是，随着这些化学化合物的误用和过度使用，病原体进化出几种机制来抵抗所有目前使用的抗感染剂。世界卫生组织最近认为耐碳青霉烯类的铜绿假单胞菌是最难治疗的感染之一，因此，未来对该物种和其他革兰氏阴性病原体的管理将需要新的，尚未发现的，抗生素作为一个细菌类群，假单胞菌属菌株（env-Ps）因其广泛的基因组含量和多样性。由于它们的遗传复杂性，次级代谢产物已被证明可以防止病原真菌的生长，分解复合物抗肿瘤化合物表现出抗肿瘤活性，并抑制广泛的细菌病原体，包括耐甲氧西林金黄色葡萄球菌和结核分枝杆菌。此外，土壤和淡水环境中占主导地位的假单胞菌，其全球丰度表明，某些有利于生态生存的特征。相比之下，铜绿假单胞菌很少被观察到，生态环境。一个可能有助于env-Ps的这种适应性效应的特征是拮抗通过生产抗菌化合物与邻近的竞争对手竞争。以前的研究表明， env-Ps能够抑制囊性纤维化（CF）衍生的病原体，包括铜绿假单胞菌，伯克霍尔德氏菌，无色杆菌属和寡养单胞菌属物种，并随后鉴定了涉及环境菌株内的拮抗活性。作为该项目的延续，来自营养丰富的假设水系统是有效的抗微生物活性的来源。事实上，初步数据显示，来自污染河流的env-Ps表现出显著的抑制CF来源的广泛耐药的能力， (XDR)病原体，包括对碳青霉烯耐药的铜绿假单胞菌。在这项研究中，一种创新的方法，可培养的细菌将用于将拮抗活性（表型）与不同的生物合成基因簇联系起来（基因型）参与抗微生物活性。通过研究env-Ps和 XDR病原体，新的拮抗因子，预计将被确定。这将通过以下方式实现：（i）隔离和测定来自污染水体的env-Ps的抗微生物活性;（ii）鉴定生物合成的参与活性的基因簇;和（iii）编码的未发现化合物的初始表征。组合的结果将用于确定选择用于未来的有效拮抗菌株的指标。有针对性的新型抗菌化合物发现。