The authors have declared that no competing interests exist.
Rather than being slowly eroded and destroyed, countless numbers of varied forms of life adapt to the diverse aspects of an ever changing environment. However, the amount of variation is maintained at a practical optimum, as too much variation would make the population ill-adapted in a stable environment, while too little variation would render it unable to adapt to environmental stresses. This principle is perhaps well exemplified by a phenomenon described for microbial cells termed “persistence” where in the face of antibiotics bacterial populations avoid extinction by harboring a subpopulation of drug-insensitive dormant cells. Although this phenomenon poses a major obstacle for the treatment of infectious diseases, persistence has been underappreciated for some time as a mechanism for bacteria to evade antibiotics. But the mechanisms of bacterial persistence are becoming clearer and so are ways to combat them. This article highlights the phenomenon of survival and persistence in cells as diverse as microbial and human and summarizes the recent advances that have taken us one step closer to understanding what persistence is all about.
In the early 1940s, it was only appropriate for Joseph Bigger to refer to a small subpopulation of bacterial cells that survived killing by penicillin, as “persisters”
Persisters have been described to arise spontaneously on the basis of random stochastic events
Recent findings from studies examining the rate of bacterial persister-cell formation over time showed that the highest frequency (∼1%) occurs in the nongrowing stationary phase
The simplest strategy to trigger entry into dormancy would be to overproduce proteins or toxins that inhibit cellular processes and growth
Perhaps, the best defined mechanism by which persister bacterial cells arise comes from the fact that DNA damage induces one or more components of the protective SOS stress response, a signaling pathway that upregulates DNA repair functions
Persister cells are highly enriched in biofilms, which are complex and highly organized surface-attached communities of microbes embedded in a polymeric matrix
Persisters are formed by all bacterial species studied and are present at 0.1%–1% in the biofilms of
Similar to the obstacle in treatment of patients that develop resistance to antimicrobials, acquisition of resistance to anticancer drugs is a major problem in cancer therapy. Most treatments, even ones that work, fail over time because tumor cells become resistant. Different mechanisms of resistance have been described for cancer cells such as modification of drug target and active extrusion of drugs by efflux pumps and, therefore, it was largely assumed that random gene changes confer resistance to drugs
In a recent study by Sharma et al.
Cancer-initiating cells are proposed as a potential resistant subpopulation because of their ability to escape the effect of drug treatment by becoming quiescent
Whether microbial or human in nature, it appears that cells have evolved analogous redundant strategies where the function of survival is assigned to a small dormant subpopulation of cells within a more rapidly proliferating population. With most of the currently available chemotherapeutic agents targeting exponentially growing cells, our therapeutic arsenal is ineffective in eradicating these dormant persister cells. Coupled with the increasing emergence of drug resistance and failure of therapies despite our medical advances, it has become critical to develop novel classes of drugs. The prospect that persisters are responsible for the persistence of chronic infections and, more gravely, recalcitrance of disseminating cancers have identified these culprit cells as viable targets for new therapies. However, such discoveries rely heavily on the depth of our understanding the nature of these intriguing cells, which would provide us with fundamental insights into the mechanisms involved in the development of drug tolerance. Inopportunely, their transient nature and low abundance, has impeded experimental advancements to elucidate the dynamics of the formation of these specialized cells that neither die nor grow. Nevertheless, the recent unearthing of an inherent tactical approach shared by diverse cellular insurgents will undoubtedly herald a new era of research into the new field of “persisters.”