Persister cells: formation, resuscitation and combative therapies

Abstract

Persister cells, or superfits, have been strongly implicated in the recalcitrance and recurrence of chronic bacterial infection through the dormant (metabolically reduced) phenotype they display and the tolerance to antimicrobial agents this dormancy grants them. The complex biochemical events that lead to the formation of persister cells are not completely understood, though much research has linked the degradation of type II toxin/antitoxin systems and reduced cellular ATP levels to the rise in stress response molecules (where (p)ppGpp is of particular interest), which induce this dormant state. The equally complex mechanism of resuscitation is initiated by the cells’ ability to sense nutrient availability via chemotaxis systems. Levels of secondary messenger proteins (i.e., cAMP) within the cell are reduced to allow the resuscitation of ribosomes, by ribosomal resuscitation factor HflX, to reinstate protein synthesis and, therefore, growth to re-populate. Techniques of superfit eradication utilise one, or more, of three approaches (i) direct killing, (ii) re-sensitising persister cells to conventional antimicrobials, or (iii) prevention of persister formation though few laboratory findings have been translated to clinical practice. This work will outline current findings in the field with a critical approach, where possible.

Molecular Mechanisms of Persistence in Protozoan Parasites

“…In addition to disease reactivation, these persistent cells stimulate the concomitant immunity, a protective response against recurrent infections [ 9 ]. Dormancy in E. coli persisters is regulated through reduced protein synthesis upon treatment with β-lactam antibiotics [ 10 , 11 ]. Among the multiple mechanisms involved in bacterial persistence, the best studied is that involving the Toxin–Antitoxin (TA) system [ 12 ].…”

“…The development of a variety of mechanisms that support the persistence of cancer cells was observed in the last decades, including epigenetic, transcriptional, and translational activities that frequently coexist and are not mutually exclusive. Persistent cells use four primary, non-exclusive tactics to avoid drug treatments, which are (1) reducing cell growth, (2) modifying cell metabolism, (3) changing cell identity, and (4) hijacking the microenvironment [ 10 ]. The initial drug treatment leads to tumor regression, which is followed by a stable timespan of “minimal residual disease” (MRD) in which a small population of cancer cells exists within tumors that are no longer regressing.…”

VariableDNAtopology is an epigenetic generator of physiological heterogeneity in bacterial populations

“…Persisters are bacterial cells that have become non‐susceptible to antimicrobial treatment without becoming resistant (Balaban et al, 2019 ; Bigger, 1944 ). They are phenotypic outliers with an environment‐specific enhanced survival trait, and they arise stochastically in a population of otherwise antimicrobial‐susceptible siblings (Hobby et al, 1942 ; Lewis, 2010 ; Wainwright et al, 2021 ). Many cellular pathways can lead to the production of persister cells, and one of these involves stochastic interference with the machinery that manages DNA topology.…”

Toxin-Antitoxin Systems: A Key Role on Persister Formation in Salmonella enterica Serovar Typhimurium

“…Several mechanisms that underly the occurrence of persisters have been proposed through experimental studies. [18][19][20][21] It is mostly associated with bacterial strategy to survive environmental stressors or antimicrobials, which results in a state of dormancy and temporal tolerant phenotype. In S. Typhimurium, several toxin-antitoxin (TA) modules have been reported to increase the proportion of persisters under host microenvironment conditions and therefore suggested to contribute to the formation of Salmonella persisters.…”