The DNA Damage Inducible SOS Response Is a Key Player in the Generation of Bacterial Persister Cells and Population Wide Tolerance

Abstract

Population-wide tolerance and persisters enable susceptible bacterial cells to endure hostile environments, including antimicrobial exposure. The SOS response can play a significant role in the generation of persister cells, population-wide tolerance, and shielding. The SOS pathway is an inducible DNA damage repair system that is also pivotal for bacterial adaptation, pathogenesis, and diversification. In addition to the two key SOS regulators, LexA and RecA, some other stressors and stress responses can control SOS factors. Bacteria are exposed to DNA-damaging agents and other environmental and intracellular factors, including cigarette smoke, that trigger the SOS response at a number of sites within the host. The Escherichia coli TisB/IstR module is as yet the only known SOS-regulated toxin-antitoxin module involved in persister formation. Nevertheless, the SOS response plays a key role in the formation of biofilms that are highly recalcitrant to antimicrobials and can be abundant in persisters. Furthermore, the dynamic biofilm environment generates DNA-damaging factors that trigger the SOS response within the biofilm, fueling bacterial adaptation and diversification. This review highlights the SOS response in relation to antimicrobial recalcitrance to antimicrobials in four clinically significant species, Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacterium tuberculosis.

Growth-dependent heterogeneity in the DNA damage response inEscherichia coli

“…The induction of the SOS response is known to have multiple consequences beyond facilitating the repair of DNA (Podlesek & Žgur Bertok, 2020), including increasing antibiotic tolerance (Dörr et al, 2009;Wu et al, 2015), modulating expression of mobile genetic elements (Beaber et al, 2004;Baharoglu et al, 2010;Fornelos et al, 2016), and increasing the rate of mutagenesis (Vaisman et al, 2012;Dapa et al, 2017;Pribis et al, 2019). Our observed growth-dependent heterogeneity in the fraction of SOS-induced cells suggests that care must be taken when making quantitative estimates of the mutation rate under conditions of sub-lethal DNA damage.…”

Colonisation dynamics of Listeria monocytogenes strains isolated from food production environments

“…In this study, recA/lexA , responsible for DNA repair and activation of the SOS response during stressful conditions in L. monocytogenes , was upregulated in three strains and one strain respectively. The SOS response is required for bacterial adaptation, diversification and pathogenesis in a majority of species and has been reported to be required for biofilm formation in E. coli , Pseudomonas aeruginosa , Staphylococcus aureus , and Mycobacterium tuberculosis 74 . Van der Veen et al 75 showed recA also influences genetic variability through mutagenic repair during continuous flow biofilms.…”

Elucidating the antimycobacterial mechanism of action of ciprofloxacin using metabolomics

“…In this study, we investigated the metabolic changes to Mtb induced by sub-MIC of ciprofloxacin, in order to better understand its mechanism of action and perhaps also the adaptations of Mtb to this, which may lead to possible drug resistance. Previous studies have identified alterations in transcription, translation, and cell wall synthesis, as part of the mechanism of action of ciprofloxacin against Mtb (51,52,135). Our metabolomics study identified metabolite markers which support previous results, as indicated by the drastic accumulation of cell wall related fatty acids, metabolites associated with an elevated gluconeogenesis and PPP flux towards DNA repair, further supported by a reduc-tion in specifically the glycogenic amino acids, and increased urea indicative of protein catabolism, as opposed to protein synthesis.…”

“…Proposedly, this is a result of stronger cleavage of FQ to the DNA-enzyme complex, which results in less single strand DNA fragments, and subsequently prevents RecA from recognizing damaged DNA and inducing the SOS regulon [32]. The SOS response assists in killing by releasing ROS [51,52], yet simultaneously activates DNA repair and creates a dormancy-state, ultimately leading to resistance. Before the SOS response can be used as an advantage, this phenomenon, and how it connects to the mechanism of ciprofloxacin, still needs to be elaborated on.…”