Arch Sisquella, Marta

Universitat Autònoma de Barcelona. Facultat de Biociències

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Figure 3. Histogram bars. Representation of the GFP induction differences between growth in LB (white bars) and growth inpresence on antibiotic (grey bars) of an strain deficient for IraD and a strain overexpressing RssB. Edited from Zeynep et al. 5Bacterial SOS Response and its role in the acquisition of antibiotic resistance and virulence factorsMarta Arch Sisquella, Grau en MicrobiologiaUniversitat Autònoma de BarcelonaINTRODUCTIONFirst described in Escherichia coli and named by Miroslav Radman in 1974 when he postulated the existence of an “error-prone”replication mechanism triggered by DNA damage or replication fork blockages1. The SOS response is controlled by two main proteins: therepressor LexA and the activator RecA. RecA binds to single-stranded DNA to form a nucleoprotein filament which leads to theautocleavage of LexA2. More than 40 genes are under control of this regulon, including low-fidelity polymerases1 (Figure 1). The inducingsignal that activates RecA and the SOS system is based on the unwinding activity of the RecBCD enzyme3.The SOS response can be triggered by various endogenous and exogenous factors, as UV irradiation, chemical compounds or organicmutagens, among others. This review is focused on the antibiotic-induced SOS response and the secondary effect that this system has inbacteria.Direct Activation of the SOS Response Indirect Activation of the SOS ResponseThe antibiotics that induce directly the SOS system are thosethat target DNA or blocks the replication fork by targeting someenzyme related to it.Quinolones: These antibiotics (Figure 2) target two essentialreplicative enzymes (DNA gyrase and DNA Topoisomerase).Their interference with these enzymes prevent the advance ofthe replication fork and induce the generation of single-strandedDNA4.Antibiotics that do not directly affect DNA replication can induce an SOSresponse in some microorganisms due to the existence of intermediatedfactors.Aminoglycosides: stimulate the production of reactive oxygen species(ROS) which target and damage DNA. These drugs induce the SOSresponse in the Vibrionaceae family, but not in Escherichia coli, due to theRpoS regulon5 (Figure 3). ClpXP regulator interact with RssB to repressRpoS genes, but IraD prevents this union and stabilize RpoS expression.It has been proved that iraD gene is not conserved in the Vibrionaceaefamily and make them more sensitive to ROS damage6.The mechanisms of action of the antibiotics are a determinant factor for the activation or not of the SOS system. Thus, each drug would have a different effect depending on the specie we study and its target on the cells.Horizontal gene transferVirulence (Staphylococcus aureus)SaPI1 is an S. aureus pathogenicity island thatencode toxic shock syndrome (TSST-1) andintegrates near the tyrB gene7. SaPI1 is relatedwith the temperate phage 80α, that when isinduced promotes the excision and theencapsulation for the transduction of the island(Figure 4) 8. The Stl repressor binds to SaPI1promoters and blocks its cycle. When the 80α isinduced by the SOS response (following thesame mechanism as phi13) a phage proteininteracts with Stl and prevents its union to thepromoters9CONCLUSIONSFigure 1. Model of the SOS induction. Edited from Lyle A.Simmons et al. 2Figure 2. Quinolone structures. Obtained from Darlika and Zhao4EFFECTS OF THE ANTIBIOTIC-INDUCED SOS RESPONSEThe widely extended use of the antibiotics for the treatment of infectious diseases has had a major role in the appearance of resistances, which directly challenge our ability to battle against these diseases. The wrong and excessiveuse of these compounds not only enhance the appearance of resistances, but in this review is proved that they also play a key role in the spread of virulence factors among bacteria and could aggravate the infectious agent we aretrying to treat, as is the case of one of the cystic fibrosis pathogens, S. aureus. The main conclusions of this review is the importance of keep studying the molecular basis of this procedures and the development of new drugs thatdo not activate the SOS system.Antibiotic resistance (Vibrio cholerae) The SXT is an integrating conjugative element(ICEs) that encode resistance to severalantibiotics and requires of recA for its excisionand transfer (Waldor). SetR is the repressor ofthe genes needed for the excision (setC andsetD). Its interaction with the active RecAfilament leads to an auto-hydrolysis of SetR andpermits the transfer of the SXT element (Figure5)10.Figure 4. Model of the SaPI1 cycle. In absence of the activebacteriophage the SaPI1 inserts into the chromosome. When thephage is induced the SaPI1 is excised and encapsulated in order to betransduced to another cell. Edited from Ruzin et al.8Figure 5. Model of the regulatory network by which theSOS response enhance the SXT transfer. Edited from JohnW. Beaber et al10.Figure 6. Adhesion to coverslips by different regulator-deficient strains. Each bar represents a different amount offibronectin in the coverslips from less to more. Edited fromBisognano et al.11Virulence (Staphylococcus aureus)Fibronectin binding proteins (FnBPs) are necessary for theattachment and encoded by two genes, one of them (fnbB)under LexA repression, among other regulator networks.Thus, in presence of ciprofloxacin RecA induce theautocleavage of LexA and permits the expression of thisvirulence factor (Figure 6). This mechanism permit that thesubpopulation of survivors to antibiotics have a majorinvasive ability11.Hemolysin β: the attP site of the prophage phi13 is located inthe hlb gene preventing its expression. The cI-like repressor ofthe lytic cycle has a C-terminal domain that interact withRecA and adopt a particular conformation in which a catalyticresidue interact with the cleavage site13 (following the samemechanism as LexA). When the phage is induced, the hlbgene can be expressed14.Figure 6. Multiplex PCR. Detection of hlb, phi13 integraseand phage-encoded protein sak before (lanes 1) and after(lanes 2) ciprofloxacin treatment. Edited from Goerke et al.14Chromosomical changesAntibiotic resistance (Persisters) Persistence: non-hereditable phenotype acquiredvia reversible epigenetic changes exhibit by asubpopulation of susceptible bacteria whichpermit to survive lethal doses of antibiotics.Persistence is induced by antibiotics and is highlyrelated with the SOS system, as demonstratedwhen a culture is treated with a SOS inducer asmytomycin C (Figure 7)15.Figure 7. Persistence induced after Mitomycin C treatment. Open barsrepresent total viable cells and grey bars are the persisters fraction.Edited from Tobias Dörr et al.151. Patel, M., Jiang, Q., Woodgate, R., Cox, M. M. & Goodman, M. F. A new model for SOS-induced mutagenesis: how RecA protein activates DNA polymerase V. Crit. Rev. Biochem. Mol. Biol. 45, 171–184 (2010).2. Simmons, L. A., Foti, J. J., Cohen, S. E. & Walker, G. C. The SOS Regulatory Network. EcoSal Plus 2008, (2008).3. Chaudhury, A. M. & Smith, G. R. Role of Escherichia coli RecBC enzyme in SOS induction. Mol. Gen. Genet. 201, 525–528 (1985).4. Drlica, K. & Zhao, X. DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol. Mol. Biol. Rev. 61, 377–392 (1997).5. Baharoglu, Z., Krin, E. & Mazel, D. RpoS Plays a Central Role in the SOS Induction by Sub-Lethal Aminoglycoside Concentrations in Vibrio cholerae. PLoS Genet. 9, (2013).6. Merrikh, H., Ferrazzoli, a E., Bougdour, a, Olivier-Mason, a & Lovett, S. T. A DNA damage response in Escherichia coli involving the alternative sigma factor, RpoS. Proc. Natl. Acad. Sci. U. S. A. 106, 611–616 (2009).8. Úbeda, C. et al. Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci. Mol. Microbiol. 56, 836–844 (2005).9. Ruzin, A., Lindsay, J. & Novick, R. P. Molecular genetics of SaPI1 – a mobile pathogenicity island in Staphylococcus aureus. 41, 365–377 (2001).10. Mir-sanchis, I. et al. Control of Staphylococcus aureus pathogenicity island excision. 85, 833–845 (2012).11. Beaber, J. W., Hochhut, B. & Waldor, M. K. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature 427, 72–74 (2004).12. Bisognano, C. et al. A RecA-LexA-dependent Pathway Mediates Ciprofloxacin-induced Fibronectin Binding in Staphylococcus aureus. J. Biol. Chem. 279, 9064–9071 (2004).13. Galkin, V. E. et al. terminal Domain. Biochemistry 385, 779–787 (2010).14. Goerke, C., Koller, J. & Wolz, C. Ciprofloxacin and trimethoprim cause phage induction and virulence modulation in Staphylococcus aureus. Antimicrob. Agents Chemother. 50, 171–177 (2006).15. Dörr, T., Lewis, K. & Vulić, M. SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genet. 5, (2009).Bibliography

Bacterial SOS response and its role in the acquisition of antibiotic resistance and virulence factors

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Bacterial SOS response and its role in the acquisition of antibiotic resistance and virulence factors

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