Phase-plastic aggresomes as tunable regulators of bacterial dormancy depth

Bacterial persistence, a major clinical challenge in chronic and biofilm-associated infections, is driven by a dormant subpopulation capable of surviving antibiotic treatment without acquiring genetic resistance. This review summarizes recent advances supporting a unifying model in which phase-plastic aggresomes-protein-RNA condensates formed via liquid-liquid phase separation-function as tunable regulators of bacterial dormancy depth. We propose that the material state of aggresomes, ranging from liquid-like to gel-like, governs cellular recovery kinetics by modulating the sequestration and availability of core cellular machinery. Under stress, aggresomes dynamically assemble in response to triggers such as ATP depletion and macrophage-derived reactive oxygen species, enabling metabolic arrest while preserving viability. Their composition evolves over time, initially favoring reversible components that support shallow dormancy, then maturing into more gel-like states that deepen dormancy and delay resuscitation. This physical continuum allows bacteria to adaptively manage fitness trade-offs between survival and recovery. We further explore how aggresome plasticity opens new therapeutic avenues for bacterial persistence, including strategies to dissolve or solidify these condensates. Understanding aggresomes as adaptive organelles offers a transformative perspective on bacterial persistence and identifies novel targets for combating recalcitrant infections.