SOS Response Induces Persistence to Fluoroquinolones in Escherichia coli

Abstract

Bacteria can survive antibiotic treatment without acquiring heritable antibiotic resistance. We investigated persistence to the fluoroquinolone ciprofloxacin in Escherichia coli. Our data show that a majority of persisters to ciprofloxacin were formed upon exposure to the antibiotic, in a manner dependent on the SOS gene network. These findings reveal an active and inducible mechanism of persister formation mediated by the SOS response, challenging the prevailing view that persisters are pre-existing and formed purely by stochastic means. SOS-induced persistence is a novel mechanism by which cells can counteract DNA damage and promote survival to fluoroquinolones. This unique survival mechanism may be an important factor influencing the outcome of antibiotic therapy in vivo. The frequent failure of antibiotic treatments is an acute public health problem. Bacteria can escape the lethal action of antibiotics by a mutation in the cell's DNA, leading to antibiotic resistance. Alternatively, they can enter a physiological state in which the antibiotics do not affect them. This phenomenon, referred to as persistence, is different from resistance because there is no genetic modification and because it is transient. Persisters are believed to form stochastically prior to antibiotic treatment. The presence of persister cells in bacterial biofilms contributes to the difficulty in treating biofilm-related infections. We investigated the persistence of Escherichia coli to one of the most widely used antibiotics, ciprofloxacin. We show that the majority of persister cells are formed in response to this antibiotic, contrary to the prevailing view of persister formation. Ciprofloxacin kills bacteria by damaging their DNA. DNA damage activates a SOS gene network, the result of which is the production of various repair proteins. We uncovered a novel part of this network that leads to the formation of tolerant persister cells. The induced tolerance as a side effect of antibiotic treatment is an effective bacterial survival strategy and is likely to contribute to recalcitrance of infections.