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.

Transcription-coupled DNA repair underlies variation in persister awakening and the emergence of resistance

“…In addition, persisters formed by the pore-forming HokB toxin were found to wake up based on pore disassembly via a combination of DsbC-mediated monomerization and DegQmediated peptide degradation, followed by membrane repolarization (Wilmaerts et al, 2019a). Furthermore, protein aggregate formation and removal were shown to be correlated with persister state entry and exit (Pu et al, 2019;Bollen et al, 2021;Dewachter et al, 2021). Based on these findings, we can infer that other persister formation pathways should be reverted to initiate persister state exit.…”

Membraneless organelles formed by liquid-liquid phase separation increase bacterial fitness

“…Protein aggregates in bacteria has been identified for many decades, but their functional role remains a debate (13,14). Protein aggregates in bacterial were initially considered as a collection of mis-folded proteins resulted from detrimental intrinsic or environmental stresses (15)(16)(17).…”

“…However, recent studies showed that protein aggregates contribute to the asymmetric division of bacteria, and shape population heterogeneity which increases bacterial fitness (14,19,20).…”

Host Cell Oxidative Stress Induces Dormant Staphylococcus aureus Persisters

“…The subsequent ATP depletion promotes protein aggregation, leading to increased lag time for cell resuscitation, correlated with the bacterial dormancy depth ( 17 ). Other phenotypes of dormant bacteria have been described, like the viable but non-culturable (VBNC) phenotype, in which cells remain viable, but in contrast to persisters, do not resume growth in medium on which they normally actively divide, unless specifically stimulated ( 13 , 19 – 21 ). Because of the similarities between persisters and VBNC cells, these phenotypes are described as part of a common dormancy continuum, in which VBNC cells represent the most dormant forms ( 21 – 23 ).…”