**1. Introduction**

Bacteria are constantly exposed to a changing and stressful environment. Coordinated responses by bacterial global regulatory systems enable their survival and adaptation [1].

In all organisms genome integrity is constantly threatened by endogenous and exogenous agents. Exogenous DNA damaging agents are physical (UV and ionizing irradiation, oxidants, drugs) and chemical (oxidizing, crosslinking, alkylating). Endogenous triggers are the result of cellular metabolism such as reactive oxygen species (ROS), stalled replication forks and defects following recombination or chromosome segregation [2, 3]. To cope with DNA damage organisms possess a number of error free and error prone mechanisms [4, 5]. Most bacteria seem to have evolved a coordinated response to DNA damage. In *Escherichia coli* the inducible DNA repair pathway is designated the SOS response and is controlled by two regulators, LexA, a repressor and RecA, an inducer. DNA damage generates an increase in single stranded DNA (ssDNA) as DNA polymerase stalls at a lesion while helicase continues unwinding DNA. RecA is activated (RecA\*) by binding to single

#### **Figure 1.**

*Exo and endogenous triggers induce the E. coli SOS response leading to antibiotic resistance, persistence, horizontal gene transfer, expression of virulence factors, intraspecies competition and biofilms.*

stranded DNA forming a nucleoprotein filament that stimulates self cleavage of LexA and in *E. coli* de-repression of more than 50 SOS genes. A hallmark of the SOS response is its temporal control. High-fidelity repair mechanisms are induced first followed by low fidelity, damage tolerance pathways involving error prone translesion DNA polymerases PolII (*polB*), PolIV (*dinB*) and PolV (*umuC, umuD*). These are active only following extensive and persistent DNA damage. While the error prone/last resort polymerases enable repair of lesions that block DNA replication by the primary replicative DNA polymerase PolIII [4, 5], they also promote an increase in mutation rate.

Even though RecA and LexA are the key SOS regulators, induction/SOS factors may also be governed by other stress response pathways namely, alternative sigma factors RpoS and RpoH of the general stress responses, the stringent response, cAMP and reactive oxgen species (ROS) [6–10].

Whilst the SOS response was initially recognized as regulating DNA damage repair, it is now well established that it plays' a much broader role. Thus, SOS error prone polymerases by promoting elevated mutation rates generate genetic diversity and adaptation. The SOS response is also involved in horizontal gene transfer, virulence factor expression, biofilms, persistence, sustained colonization of the mammalian gut, controls toxin-antitoxin systems as well as intraspecies competition and phenotypic variation (**Figure 1**) [5, 11, 12].

## **2. Mutagenesis and antibiotic resistance**

Antibiotic resistance is one of the most serious global health threats. Resistance occurs by mutation of resident genes or/and by uptake of resistance genes. Antibiotic resistance mechanisms belong to one of several classes with resistance genes encoded on chromosomes and mobile genetic elements such as plasmids, transposons and integrons. As stated above, the error prone translesion DNA polymerases PolII, PolIV and PolV allow translesion DNA replication but also promote an increased level of mutation, significant for evolution of antibiotic resistance.

Exposure of bacteria to antibiotics, even at subinhibitory concentrations, has been shown to increase mutation and recombination frequencies via the SOS

response [13, 14]. In *E. coli* as well as a number of other clinically significant bacterial species, some of the most common antibiotics have been shown to induce the SOS response and mutagenesis [15, 16]. Exposure of environmental bacteria to antibiotics, even subinhibitory levels, could thus generate variants with higher rates of genetic modifications and select for resistance.
