Sub-Lethal Exposures to Metal and Metal-Oxide Nanoparticles Lead to Antibiotic Resistance in Engineered Environments: A Mechanistic Study

工程纳米材料的安全性和抗生素耐药性是全球关注的两个问题。 纳米材料是具有纳米尺度直径的颗粒材料，并且它们广泛地用于工业和消费品中。 然而，一些纳米材料已被证明可以杀死有益细菌。 抗生素耐药性是微生物使抗生素失活的能力，从而使有害细菌存活。 抗生素耐药性的影响估计每年给美国经济造成数十亿美元的损失。该研究项目将研究纳米材料是否可以刺激致病细菌的抗生素耐药性。 这些调查将通过多阶段实验研究来完成，以确定纳米材料的毒性浓度，并描述微生物对纳米材料的适应性反应。 该项目的成功完成将促进我们对纳米材料如何刺激抗生素耐药性的理解。 研究人员将开发一门关于抗生素耐药性的跨学科本科课程，其中包括关于抗生素耐药性的专家小组讨论，关于适应性耐药性的实验室模块，以及学生制作的播客，以应对抗生素耐药性的挑战。 多名本科生将通过毕业生与本科生（GLUE）计划参与研究活动。 该项目的成功完成将促进我们对抗生素耐药性和纳米材料之间联系的理解，并使公众，监管机构和行业能够就使用含有纳米材料的产品做出明智的决定，以保护人类健康。抗生素耐药性和工程纳米材料的安全性是全球关注的问题。 该研究项目将评估金属和金属氧化物工程纳米材料是否会刺激细菌的抗生素耐药性。 这一目标将通过研究金属和金属氧化物工程纳米材料存在下铜绿假单胞菌、金黄色葡萄球菌和大肠杆菌中可遗传的遗传变化引起的抗生素应激基因和突变抗生素耐药性的表达来实现。 这项工作的具体目标是：一）确定金属和金属氧化物纳米材料及其相关溶解金属对嗜热菌的亚致死浓度;二）评估接触亚致死纳米材料或溶解金属浓度的嗜热菌适应性抗性的发生和机制基础; iii）评估嗜热细菌对亚致死纳米材料或溶解金属暴露的时间转录响应; iv）评估由于亚致死纳米材料或溶解金属暴露导致的嗜热细菌中的突变抗性;以及v）探索由于亚致死纳米材料或溶解金属暴露导致的生物膜中的适应性抗性。 重要的是，该项目将区分“完整”纳米材料和溶解金属对抗生素耐药性发展的影响。该奖项反映了NSF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。

The safety of engineered nanomaterials and antibiotic resistance are two issues of global concern. Nanomaterials are particles materials that have a diameter on the nanometer scale, and they are used widely in industry and in consumer products. However, some nanomaterials have been shown to kill beneficial bacteria. Antibiotic resistance is the ability of microorganisms to deactivate antibiotics, thus allowing harmful bacteria to survive. The effects of antibiotic resistance create an estimated billion-dollar in annual costs to the United States economy. This research project will study the question of whether nanomaterials can stimulate antibiotic resistance in disease-causing bacteria. These investigations will be accomplished through multi-phase experimental studies to identify toxic concentrations of nanomaterials and to characterize the adaptive responses of microorganisms to nanomaterials. Successful completion of this project will advance our understanding of how nanomaterials stimulate antibiotic resistance. The researchers will develop an interdisciplinary undergraduate course on antibiotic resistance that incorporates an expert panel discussion on antibiotic resistance, a lab module on adaptive resistance, and student-produced podcasts that address challenges in antibiotic resistance. Multiple undergraduate students will be engaged in the research activities through the Graduates Linked with Undergraduates (GLUE) program. Successful completion of this project will advance our understanding of the link between antibiotic resistance and nanomaterials and enable the public, regulatory agencies, and industry to make informed decisions about the use of products containing nanomaterials to protect human health. The twin problems of antibiotic resistance and the safety of engineered nanomaterials are issues of global concern. This research project will assess whether metal and metal-oxide engineered nanomaterials stimulate antibiotic resistance in bacteria. This objective will be achieved by studying the expression of antibiotic stress genes and mutative antibiotic resistance due to hereditable genetic changes in Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli in the presence of metal and metal-oxide engineered nanomaterials. The specific objectives of the work are to: i) determine sub-lethal concentrations of metal and metal-oxide nanomaterials and their associated dissolved metals for planktonic bacteria; ii) assess the occurrence and mechanistic basis for adaptive resistance in planktonic bacteria exposed to sub-lethal nanomaterial or dissolved metal concentrations; iii) evaluate the temporal transcriptional response of planktonic bacteria to sub-lethal nanomaterial or dissolved metal exposures; iv) assess mutative resistance in planktonic bacteria due to sub-lethal nanomaterial or dissolved metal exposures; and v) explore adaptive resistance in biofilms due to sub-lethal nanomaterial or dissolved metal exposures. Importantly, this project will differentiate between the impact of "intact" nanomaterials and that of dissolved metals on antibiotic resistance development.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.