Sequestration of SerRS through LLPS Impairs Localized Translation and Contributes to Antibiotic Persistence
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Antibiotic-tolerant persisters contribute to the emergence of resistance, posing a significant challenge to the efficacy of antibiotic therapies. Despite extensive research, the mechanisms underlying persistence remain inadequately understood. By tracking the evolution of exponential-phase bacterial populations subjected to intermittent high-dose ertapenem exposure, we characterized the evolved strains in terms of tolerance. Mutant strains, harboring mutations in the seryl-tRNA synthetase gene ( serS) , exhibited abrupt growth arrest upon serine depletion during exponential growth, resembling the persistence phenotype induced by serine hydroxamate (SHX). Under serine starvation, the mutated SerRS protein was sequestrated into liquid-liquid phase separation (LLPS)-driven condensates, disrupting their composition and impairing localized translation. This event precipitated growth arrest and dormancy in the SerS T strain, triggering persistence. Our findings reveal an unrecognized role for aminoacyl-tRNA synthetases (aaRSs) in modulating bacterial condensates and provide insights into the molecular mechanisms underlying bacterial persistence.
Graphic abstract
SerRS Recruitment Disrupts Localized Translation in DeaD-marked Condensates.
Upon serine starvation, SerRS T partitions into LLPS-driven DeaD-marked condensates, impairing their localized translation activity and suggesting mechanisms underlying persistence arising during exponential phase. These evolutionarily conserved condensates orchestrate a robust translation program to enable stress responses and instruct cell fate decisions in bacterial populations.
