The power of dying slowly - persistence as unintentional dormancy

Abstract Persistence is a state of bacterial dormancy where cells with low metabolic activity and growth rates are phenotypically tolerant to antibiotics and other cytotoxic substances. Given its obvious advantage to bacteria, several researchers have been looking for the genetic mechanism behind persistence. However, other authors argue that there is no such mechanism and that persistence results from inadvertent cell errors. In this case, the persistent population should decay according to a power-law with a particular exponent of −2. Studying persisters’ decay is, therefore, a valuable way to understand persistence. Here we simulated the fate of susceptible cells in laboratory experiments in the context of indirect resistance. Eventually, under indirect resistance, detoxifying drug-resistant cells save the persister cells that leave the dormant state and resume growth. The simulations presented here show that, by assuming a power-law decline, the exponent is close to −2, which is the expected value if persistence results from unintentional errors. Whether persisters are cells in a moribund state or, on the contrary, result from a genetic program, should impact the research of anti-persistent drugs. Author Summary Persistence, a form of bacterial dormancy, was discovered in the early days of the antibiotic era. Thanks to dormancy, these cells often evade antibiotic therapy and the immune system. However, despite its clinical importance, this phenotype’s nature is still under debate. Arguably, the prevailing view is that persistence is an evolved (selected for) bet-hedging mechanism to survive in the presence of cytotoxic agents such as antibiotics. In that case, the persister population should decay exponentially, although at a much slower pace than the non-persister population. A few authors recently advanced an alternative hypothesis: bacterial persistence results from many malfunctions and cell division errors. In this case, persistent populations should decay according to a power-law with exponent of −2, that is, according to 1/t 2 . Here we simulated the fate of susceptible bacterial cells in the presence of bactericidal antibiotics in the context of indirect resistance based on laboratory experiments performed earlier. By showing that the dynamics of persister cells is consistent with 1/t 2 , our results corroborate the hypothesis that the phenomenon of bacterial persistence is an accidental consequence of inadvertent cell problems and errors. If confirmed, this conclusion should impact the research strategies of anti-persistent drugs. “The following day, no one died. This fact, being absolutely contrary to life’s rules, provoked enormous and, in the circumstances, perfectly justifiable anxiety in people’s minds, for we have only to consider that in the entire forty volumes of universal history there is no mention, not even one exemplary case, of such a phenomenon ever having occurred…” Death with interruptions José Saramago (2005) Nobel Prize for Literature 1998