Adenosine Triphosphate-Coated Gold Nanoclusters as Evolutionary Adjuvants Suppress fusA-Mediated Antibiotic...

Mutations in the fusA gene are crucial pathways for high-level aminoglycoside resistance, creating a major barrier to treating chronic cystic fibrosis (CF) lung infections. While lab models often failed to replicate the translational gap seen in advanced clinical strains, we found that metabolic dormancy, rather than physical biofilm structure, was the key survival strategy in CF isolates. To address this, we introduced AuNC@ATP, a gold nanocluster platform that acted as an evolutionary adjuvant. AuNC@ATP remained highly effective against bacteria in serum-rich environments, where traditional nanomaterials usually failed. Importantly, whole-genome profiling revealed that AuNC@ATP constrained adaptive mutational trajectories. While tobramycin monotherapy was selected for fusA-associated adaptation, AuNC@ATP co-treatment suppressed the emergence of fusA mutations, and no transversion events were detected in the co-treatment lineage. By trapping pathogens in a sub-optimal genetic state, AuNC@ATP offered a dual-action strategy that provided immediate clinical benefits while maintaining the long-term usefulness of existing antibiotics.