Protein Aggregation as a Bacterial Strategy to Survive Antibiotic Treatment

Abstract

While protein aggregation is predominantly associated with loss of function and toxicity, it is also known to increase survival of bacteria under stressful conditions. Indeed, protein aggregation not only helps bacteria to cope with proteotoxic stresses like heat shocks or oxidative stress, but a growing number of studies suggest that it also improves survival during antibiotic treatment by inducing dormancy. A well-known example of dormant cells are persisters, which are transiently refractory to the action of antibiotics. These persister cells can switch back to the susceptible state and resume growth in the absence of antibiotics, and are therefore considered an important cause of recurrence of infections. Mounting evidence now suggests that this antibiotic-tolerant persister state is tightly linked to-or perhaps even driven by-protein aggregation. Moreover, another dormant bacterial phenotype, the viable but non-culturable (VBNC) state, was also shown to be associated with aggregation. These results indicate that persisters and VBNC cells may constitute different stages of the same dormancy program induced by progressive protein aggregation. In this mini review, we discuss the relation between aggregation and bacterial dormancy, focusing on both persisters and VBNC cells. Understanding the link between protein aggregation and dormancy will not only provide insight into the fundamentals of bacterial survival, but could prove highly valuable in our future battle to fight them.

Keywords: VBNC; amorphous aggregate; amyloid; antibiotic tolerance; dormancy; persistence; stress response.

FIGURE 1

A model depicting the role of protein aggregation in the formation and awakening of dormant cells. Progressive protein aggregation is proposed to induce the shift from sensitive to dormant cells. Aggregation can induce the switch from sensitive cells to the shallowly dormant persister state. Further development of the aggregates can cause a shift from persister cells to the deeper dormant VBNC state. This aggregation-induced dormancy renders cells tolerant to antibiotics. This tolerance is likely caused by the sequestration of proteins in the cell, thereby shutting down different important cellular pathways. To wake up again, these dormant cells likely first need to remove the aggregates. To perform this disaggregation, bacteria make use of chaperones.

FIGURE 2

Different types of protein aggregations. When proteins are—at least partially—unfolded or misfolded, they can expose their aggregation-prone regions (APRs). Interaction of APRs of different proteins results in the formation of intermolecular β-sheets that cause aggregation. Amyloid aggregates are highly ordered as their β-sheets run perpendicular to the central axis of the aggregate. Amorphous aggregates also contain some β-structures but lack this long-range order.