Are Bacterial Persisters Dormant Cells Only?

Abstract

Bacterial persisters are a sub-population of phenotypic variants that tolerate high concentrations of antibiotics within the genetically homogeneous cells. They resume division upon the removal of drugs. Bacterial persistence is one of major causes of antibiotic treatment failure and recurrent infection. Cell dormancy, triggered by toxin/antitoxin pair, (p)ppGpp, SOS response and ATP levels, is known to be the mechanistic basis for persistence. However, recent studies have demonstrated that bacteria with active metabolism can maintain persistence by lowering intracellular antibiotic concentration via an efflux pump. Additionally, others and our work have showed that cell wall deficient bacteria (CWDB), including both L-form and spheroplasts that produced by β-lactam antibiotics, are associated with antibiotic persistence. They are not dormant cells as their cell walls have been completely damaged. In this review, we discuss the various types of persisters and highlight the contribution of non-walled bacteria on bacterial persistence.

Keywords: L-form; cell wall deficient bacteria; dormancy; persister; spheroplast.

FIGURE 1

Formation of bacterial persistence via cell dormancy. Various pathways could trigger bacterial cells into dormant state upon antibiotic stress. A considerable number of TA modules could free toxins upon stresses, which result in persister formation by inhibiting DNA replication, or transcription, or translation processes, or downregulating proton motive force (PMF) that is under the control of SOS response. Dormancy could be also triggered by accumulated alarmone molecules and decreased intracellular ATP levels. The gray layers represent the outer membrane and inner membrane, respectively, and the red square linkage represents the peptidoglycan and periplasmic space.

FIGURE 2

Activated efflux systems contribute to bacterial persistence. Different from cell dormancy, bacterial persisters can also employ efflux pumps with enhanced activities to defend antibiotic killing by exporting intracellular antibiotics, resulting in lower intracellular concentration of drugs that enable bacteria to survive.

FIGURE 3

Persisters formation through CWDB. Upon antibiotic treatment, a portion of persisters maintain intact cellular structure through forming dormancy and/or active efflux pumps. In addition, some bacteria could survive after their cell walls being damaged and form spheroplast or L-form. Through an unknown mechanism, such bacteria could persist in vivo or in vitro. Persister cells with intact cell structure or cell wall deficiency are separated by black dot line.