The role of metabolism in bacterial persistence

Abstract

Bacterial persisters are phenotypic variants with extraordinary tolerances toward antibiotics. Persister survival has been attributed to inhibition of essential cell functions during antibiotic stress, followed by reversal of the process and resumption of growth upon removal of the antibiotic. Metabolism plays a critical role in this process, since it participates in the entry, maintenance, and exit from the persister phenotype. Here, we review the experimental evidence that demonstrates the importance of metabolism to persistence, highlight the successes and potential of targeting metabolism in the search for anti-persister therapies, and discuss the current methods and challenges to understand persister physiology.

Keywords: antibiotic tolerance; bacterial persistence; metabolism; nutrient environment; ppGpp.

Figure 1

Persister metabolic program. Persisters can be pre-existing in a bacterial population (Balaban et al., 2004), formed in response to stress, such as stresses that activate the stringent response (Amato et al., 2013), and induced during antibiotic treatment (Dörr et al., ; Orman and Brynildsen, 2013a). Maintenance of the persister state for the duration of the antibiotic treatment requires temporary inhibition of essential cell functions; however, persisters must remain culturable, which requires a minimal adenylate charge to be sustained (Chapman et al., 1971) and damage to be repaired (Nystrom and Gustavsson, 1998). Upon removal of the antibiotic, persisters exit their tolerant state and give rise to a bacterial population of identical antibiotic susceptibility as the original population (Balaban et al., 2004).