New-found fundamentals of bacterial persistence

Abstract

Persister cells display tolerance to high doses of bactericidal antibiotics and typically comprise a small fraction of a bacterial population. Recently, evidence was provided for a causal link between therapy failure and the presence of persister cells in chronic infections, underscoring the need for research on bacterial persistence. A series of recent breakthroughs have shed light on the multiplicity of persister genes, the contribution of gene expression noise to persister formation, the importance of active responses to antibiotic tolerance and heterogeneity among persister cells. Moreover, the development of in vivo model systems has highlighted the clinical relevance of persistence. This review discusses these recent advances and how this knowledge fundamentally changes the way in which we will perceive the problem of antibiotic tolerance in years to come.

Biofilm-Related Infections: Bridging the Gap between Clinical Management and Fundamental Aspects of Recalcitrance toward Antibiotics

“…4C). Then, when the population meets environmental triggers inducing stringent or SOS responses, the basal level of expression increases, leading to an increase in the percentage of cells reaching the threshold (94,159). This hypothesis has been supported by experiments performed with TA modules that also demonstrate that the amount by which the threshold is exceeded determines the duration of dormancy (160).…”

“…Even when enrichment is significant, it is important that not all dormant bacteria are persisters; conversely, all persisters do not necessarily correspond to dormant cells (93). Therefore, it is likely that passive dormancy per se is not entirely responsible for the persister phenotype (94). A recent study confirmed these findings by using flow cytometry sorting of E. coli cells based on their level of metabolic activity and/or cell division (95).…”

“…The deletion of hipB is lethal because of HipA toxicity, suggesting that HipB is the repressor of the operon (105). Note that deletion of the complete hip locus has no effect on persister frequency in exponentially growing bacteria, possibly because of TA module redundancy (94,105). Another explanation is that the HipBA module contributes to the persister switch only in cases of After a rapid decrease, surviving cell fractions reach a plateau corresponding to persisters (red curve).…”

“…If a resistant mutant were present, it would be able to grow in the presence of the antibiotic (dotted line). Panel B was inspired by previous reports (13,31,94). slow growth (stationary-phase cultures) (106).…”

The Formation of Streptococcus mutans Persisters Induced by the Quorum-Sensing Peptide Pheromone Is Affected by the LexA Regulator

“…Persister cells are formed through random intrinsic fluctuations of protein levels, such as the well-studied stable toxins expressed by chromosomal toxin-antitoxin (TA) modules (10)(11)(12)(13). Spontaneous gene expression and noise during transcription and translation, amplified by feedback regulatory processes, also give rise to fluctuating protein levels of persister genes that result in a dormant multidrug-tolerant state (3,14). Since the formation of persister cells is a result of a variety of mechanisms, the subpopulation of persisters is heterogenous.…”