Eradication of bacterial persister cells by leveraging their low metabolic activity using adenosine triphosphate coated gold nanoclusters

• Published in: Nano today 2023-08, Vol.51, p.101895, Article 101895
• Main Authors: Bekale, Laurent A., Sharma, Devesh, Bacacao, Brian, Chen, Jing, Maria, Peter L. Santa
• Format: Article
• Language: English
• Subjects: Antibiotic resistance; Antimicrobial Gold nanoclusters; Lipid homeostasis; Outer membrane proteins; Persister cells
• ISSN: 1748-0132; 1878-044X
• DOI: 10.1016/j.nantod.2023.101895

Bacteria first develop tolerance after antibiotic exposure; later genetic resistance emerges through the population of tolerant bacteria. Bacterial persister cells are the multidrug-tolerant subpopulation within an isogenic bacteria culture that maintains genetic susceptibility to antibiotics. Because of this link between antibiotic tolerance and resistance and the rise of antibiotic resistance, there is a pressing need to develop treatments to eradicate persister cells. Current anti persister cell strategies are based on the paradigm of "awakening" them from their low metabolic state before attempting eradication with traditional antibiotics. Herein, we demonstrate that the low metabolic activity of persister cells can be exploited for eradication over their metabolically active counterparts. We engineered gold nanoclusters coated with adenosine triphosphate (AuNC@ATP) as a benchmark nanocluster that kills persister cells over exponential growth bacterial cells and prove the feasibility of this new concept. Finally, using AuNC@ATP as a new research tool, we demonstrated that it is possible to prevent the emergence of antibiotic-resistant superbugs with an anti-persister compound. Eradicating persister cells with AuNC@ATP in an isogenic culture of bacteria stops the emergence of superbug bacteria mediated by the sub-lethal dose of conventional antibiotics. Our findings lay the groundwork for developing novel nano-antibiotics targeting persister cells, which promise to prevent the emergence of superbugs and prolong the lifespan of currently available antibiotics. [Display omitted] •The low metabolic activity of persister cells can be exploited for eradication over their metabolically active counterparts.•AuNC@ATP kills persister cells over exponential growth bacterial cells.•Bacteria become more sensitive to AuNC@ATP when they enter a dormant state which would typically allow them to survive exposure to traditional antibiotics.•Eradicating persister cells with AuNC@ATP in an isogenic culture of bacteria stops the emergence of superbug bacteria mediated by the sub-lethal dose of conventional antibiotics.•AuNC@ATP has antimicrobial activity attributable to the stress response that builds up from unfolded outer membrane proteins accumulation in the periplasm leading to the disruption of bacterial membranes by altering lipid homeostasis and asymmetry.