Serving Two Masters; The Role of Trade-Offs in the Evolution of Bacteriophage/Metal Resistance in Escherichia Coli

侍奉两位主人；

• 批准号: 2132240
• 负责人: LIESL JEFFERS-FRANCIS
• 金额: $ 62.85万
• 依托单位: North Carolina Agricultural & Technical State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2132240&HistoricalAwards=false
• 关键词: Serving; Two; Masters; Role; Trade

Antimicrobial resistance (AMR) is a major public health challenge that portends danger in healthcare delivery, as scientific reviews on antibiotic resistance predicted a likelihood of 10 million mortalities per year by 2050. Post-antibiotic era, which was brought about by the spread of resistance to traditional antibiotics, has prompted the quest for new antimicrobial substances. Interest in metallic antimicrobial materials such as Ag, Cu, Zn, and excess Fe (II, III) are growing due to their potential to control pathogenic and multi-drug resistant bacteria. However, we do not know if utilizing these materials can lead to genetic adaptations that produce even more dangerous bacterial strains. Early studies that proposed ionic and nanoparticle metals as new antimicrobials were deficient because they did not consider the evolutionary dynamics of populations exposed to toxic materials. Another alternative to traditional antibiotics are bacteriophages, which are viruses that infect and kill bacteria. Bacteriophage therapy recently gained more attention because of the emergence of multi-drug resistant bacteria. Our preliminary findings suggest that experimental evolution of E. coli in Fe (III) yielded variants which were better fitted in antibiotics. If trade-offs exist in pattern of resistance, we expected our Fe (III) + T7 phage variant to trade T7 phage resistance for susceptibility to antibiotics. The goals of the present proposed study are to unravel the evolutionary dynamics of potential trade-offs between Fe (III) and phage resistance in E. coli. This project will contribute to ongoing recruitment and retention of underrepresented undergraduate and graduate minority students in STEM, including bioinformatics, genomics, microbiology, evolutionary biology and engineering. Opportunities will include technical training, professional development activities, presentations at national conferences, and educating and recruiting their peers. Also, community science outreach activities are planned, including participation in the North Carolina Science Olympiad at a local K-12 school as well as recruitment of a high school student to perform research on this project as part of their senior science project.The mechanism of trade-offs in antibacterial resistance evolution under multi-selective pressures, including bacteriophages, antibiotics and heavy metals is incompletely understood. Therefore, the long-term goal of this project is to evaluate bacterial evolution under multi-selective pressures, specifically heavy metal (iron) and bacteriophage. The central hypothesis is that evolution of resistance to iron will consequently confer susceptibility to bacteriophage infection and evolution of bacteriophage resistance will confer susceptibility to iron and a combination of iron and bacteriophage resistance will affect susceptibility of evolutionary resistance to either. This trade-off mechanism is well known in evolutionary studies as a fitness epistasis or genetic background effect and is implicated in driving evolution of extensively drug resistant microbes. Understanding how bacteria evolve resistance to biocides is an important aspect of the sustainability of any control measure. For example, if the bacteria develop completely independent responses to iron and bacteriophage then this has profound implications for how any biocide should be deployed. If there are trade-offs associated with multi-selective pressures then the sustainability of each resistant strain may be enhanced by the use of combination approaches.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

抗菌素耐药性（AMR）是一项重大公共卫生挑战，预示着卫生保健服务的危险，因为关于抗生素耐药性的科学评论预测，到2050年，每年可能有1000万人死亡。传统抗生素耐药性的蔓延带来了后抗生素时代，促使人们寻求新的抗菌物质。由于具有控制致病性和多重耐药细菌的潜力，人们对金属抗菌材料如银、铜、锌和过量铁（II， III）的兴趣正在增长。然而，我们不知道利用这些材料是否会导致产生更危险的细菌菌株的遗传适应。早期提出离子和纳米颗粒金属作为新型抗菌剂的研究存在缺陷，因为它们没有考虑暴露于有毒物质的种群的进化动力学。传统抗生素的另一种替代品是噬菌体，这是一种感染并杀死细菌的病毒。近年来，由于多种耐药细菌的出现，噬菌体治疗受到越来越多的关注。我们的初步研究结果表明，大肠杆菌在Fe （III）中的实验进化产生了更适合抗生素的变体。如果在耐药性模式中存在权衡，我们预计我们的Fe (III) + T7噬菌体变体会以T7噬菌体耐药性换取对抗生素的敏感性。本研究的目的是揭示大肠杆菌中铁（III）和噬菌体耐药性之间潜在权衡的进化动力学。该项目将有助于持续招募和留住STEM专业中代表性不足的本科生和研究生，包括生物信息学、基因组学、微生物学、进化生物学和工程学。机会包括技术培训、专业发展活动、在全国会议上发表演讲，以及教育和招聘他们的同行。此外，还计划开展社区科学推广活动，包括在当地一所K-12学校参加北卡罗莱纳科学奥林匹克竞赛，以及招募一名高中生对该项目进行研究，作为他们高年级科学项目的一部分。在包括噬菌体、抗生素和重金属在内的多重选择压力下，抗菌药物耐药性进化的权衡机制尚不完全清楚。因此，该项目的长期目标是评估细菌在多选择压力下的进化，特别是重金属（铁）和噬菌体。核心假设是，对铁的抗性进化将导致对噬菌体感染的易感性，而噬菌体抗性的进化将导致对铁的易感性，铁和噬菌体抗性的结合将影响对任何一种进化抗性的易感性。这种权衡机制在进化研究中被称为适应度上位或遗传背景效应，并与驱动广泛耐药微生物的进化有关。了解细菌如何进化出对杀菌剂的抗性是任何控制措施可持续性的一个重要方面。例如，如果细菌对铁和噬菌体产生完全独立的反应，那么这对如何部署任何杀菌剂都具有深远的意义。如果存在与多选择压力相关的权衡，那么使用组合方法可以增强每种抗性菌株的可持续性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。