Collaborative Research: Using Anisotropic Surface Coating of Nanoparticles to Tune Their Antimicrobial Activity

致病菌中抗菌素/抗生素耐药性的迅速上升对全球公共卫生构成威胁。当细菌和真菌进化到不再对抗生素产生反应并继续生长时，就会产生抗微生物药物耐药性。每年仅在美国，抗微生物细菌或真菌就会导致280多万人感染，35000多人死亡。开发传统抗生素的替代品对于应对这一全球挑战至关重要。该合作项目支持基础研究，以开发一种新型抗菌纳米颗粒来对抗耐抗生素细菌。这些纳米粒子的独特之处在于，它们显示出一层不均匀的疏水和带正电的分子涂层。这种纳米颗粒有望通过新的抗生素机制发挥作用，而这种机制不太可能导致细菌获得性耐药。研究小组将结合实验和计算模型来阐明这些纳米颗粒与细菌的相互作用如何依赖于纳米颗粒的非均匀表面化学和细菌的细胞壁化学。这项研究的机制理解将指导抗菌纳米颗粒的合理设计，以对抗广泛的致病菌。通过将纳米科学研究与教育和推广活动相结合，该合作项目概述了促进批判性思维和增加STEM多样性的跨学科方法。这些方法包括开发将科学教学与艺术相结合的本科入门课程，一个针对农村地区K-12学生的合作推广项目，以及培训下一代研究人员，特别是代表性不足的少数群体。开发广谱抗菌纳米颗粒具有挑战性，因为单个纳米颗粒的设计不可能是一种适用于所有细菌的万能溶液。相反，我们需要的是能够调节抗菌活性以适应细菌多样性的纳米颗粒。这个合作项目的重点是开发一种新的策略，通过利用纳米颗粒上配体的各向异性组织来调节纳米颗粒与细菌的相互作用。具体来说，实验将与分子动力学模拟相结合，以研究两亲性纳米颗粒与模型细菌膜和多种革兰氏阴性菌株的相互作用，其中许多菌株对大多数现有抗生素具有耐药性。预期结果将为两亲性纳米颗粒的抗菌机制建立结构-活性关系。这种新的认识将使抗菌纳米颗粒的开发和优化成为可能，这些纳米颗粒比现有的纳米颗粒更有效，而且其效果是可调节的。该项目的教育和推广目标是发展跨学科的方法，以促进批判性思维和增加STEM的多样性。这些方法包括创新本科入门课程，将艺术与科学教学结合起来，开展面向农村地区K-12学生的合作推广项目，以及培训下一代研究人员，特别强调未被充分代表的少数群体的参与。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。

The rapid rise in antimicrobial/antibiotic resistance in pathogenic bacteria is a global public health threat. Antimicrobial resistance occurs when bacteria and fungi evolve to stop responding to antibiotics and to continue to grow. Each year in the US alone, antimicrobial-resistant bacteria or fungi cause infection in more than 2.8 million people and more than 35,000 deaths. Developing alternatives to traditional antibiotics is critical for addressing this global challenge. This collaborative project supports fundamental research to develop a new type of antimicrobial nanoparticle to combat antibiotic-resistant bacteria. These nanoparticles are unique in that they display a non-uniform coating of hydrophobic and positively charged molecules. Such nanoparticles are expected to act through novel antibiotic mechanisms that are less likely to cause acquired drug resistance in bacteria. The research team will combine experiments with computational modeling to elucidate how interactions of these nanoparticles with bacteria depend on the non-uniform surface chemistry of nanoparticles and the cell wall chemistry of bacteria. The mechanistic understanding from this study will guide the rational design of antimicrobial nanoparticles against a wide range of pathogenic bacteria. By integrating nanoscience research with educational and outreach activities this collaborative project outlines interdisciplinary approaches to promote critical thinking and increase diversity in STEM. These approaches include the development of introductory undergraduate courses that integrate science teaching with art, a collaborative outreach project to K-12 students in rural areas, and training of the next generation of researchers, especially underrepresented minority groups. Developing broad-spectrum antimicrobial nanoparticles is challenging because a single nanoparticle design cannot be a one-size-fits-all solution effective against all bacteria. Instead, nanoparticles whose antimicrobial activity can be tuned to match the bacterial diversity are needed. This collaborative project is focused on developing a new strategy to tune nanoparticle-bacteria interactions by using the anisotropic organization of ligands on nanoparticles. Specifically, experiments will be combined with molecular dynamics simulations to investigate interactions of amphiphilic nanoparticles with model bacterial membranes and a diverse selection of Gram-negative bacterial strains, many of which are resistant to most available antibiotics. The expected results will establish the structure-activity relationship governing the antimicrobial mechanisms of the amphiphilic nanoparticles. Such new understanding will enable the development and optimization of antimicrobial nanoparticles that are potentially more potent than existing ones and whose effects are tunable. The educational and outreach goal of this project is to develop interdisciplinary approaches to promote critical thinking and increase diversity in STEM. These approaches include innovation of introductory undergraduate courses by integrating art with science teaching, a collaborative outreach project to K-12 students in rural areas, and training of next generation of researchers with a particular emphasis on the involvement of underrepresented minority groups.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.