What we study: A growing body of research indicates that certain nanoparticles (NPs) designed at molecular and nanometer scales are effective at altering, disrupting, and in some cases destroying bacteria, fungi, and viruses. While multiple mechanisms of action of NPs against pathogens have been described, the fundamental physics and chemistry linking the variety of NP geometrical, chemical, and other features that cannot be observed in small molecules to specific actions remains a mystery. We adapt standard molecular microbiology techniques for the unique aspects of working with NPs to determine the specific biochemical and biophysical mechanisms of action. That knowledgebase is then used to optimize and improve on the design of the next generation of NPs

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Why it matters: Since the discovery of penicillin the time from discovery of a new class of antibiotics to the observation of resistance as steadily decreased. The current process for antimicrobial drug discovery is too narrow in scope to meet the needs of rapidly evolving bacteria and viruses. Despite decades of screening of small molecular libraries for antibacterial function, there have only been 1-2 new classes antibiotics. The use of NPs increases the potential variable space for antimicrobial therapeutic design.

 

Our key contributions: We have reimagined NPs to be more than mere delivery vehicles but rather active agents in and of them themselves. We demonstrated for the first time that NPs can be engineered with shape-specific enzyme inhibition capabilities that can be modeling with traditional small molecule enzyme kinetic formalisms (e.g., Michaelis-Menten) and that NP shape is as or more important that size with respect to antimicrobial potency. We dispelled common but unfounded notions about NP mechanisms of action through rigorous mechanistic studies. Finally, we have been inspired to engineer NPs that mimic innate immune mediators (e.g., neutrophil extracellular traps or NETS).