Staphylococcus aureus SOS response: Activation, impact, and drug targets

Abstract

Staphylococcus aureus is a common cause of diverse infections, ranging from superficial to invasive, affecting both humans and animals. The widespread use of antibiotics in clinical treatments has led to the emergence of antibiotic-resistant strains and small colony variants. This surge presents a significant challenge in eliminating infections and undermines the efficacy of available treatments. The bacterial Save Our Souls (SOS) response, triggered by genotoxic stressors, encompasses host immune defenses and antibiotics, playing a crucial role in bacterial survival, invasiveness, virulence, and drug resistance. Accumulating evidence underscores the pivotal role of the SOS response system in the pathogenicity of S. aureus. Inhibiting this system offers a promising approach for effective bactericidal treatments and curbing the evolution of antimicrobial resistance. Here, we provide a comprehensive review of the activation, impact, and key proteins associated with the SOS response in S. aureus. Additionally, perspectives on therapeutic strategies targeting the SOS response for S. aureus, both individually and in combination with traditional antibiotics are proposed.

Keywords

antibiotic-resistant / drug target / error-prone repair / SOS response / Staphylococcus

References

[1] Ha KP, Clarke RS, Kim GL, Brittan JL, Rowley JE, Mavridou DAI, et al. Staphylococcal DNA repair is required for infection. mBio. 2020; 11:e02288-20.

[2] Andriole VT. The quinolones: past, present, and future. Clin Infect Dis. 2005; 41: S113–S119.

[3] Lenhart JS, Schroeder JW, Walsh BW, Simmons LA. DNA repair and genome maintenance in Bacillus subtilis. Microbiol Mol Biol Rev. 2012; 76:530–564.

[4] Gaupp R, Ledala N, Somerville GA. Staphylococcal response to oxidative stress. Front Cell Infect Microbiol. 2012; 2:33.

[5] Baharoglu Z, Bikard D, Mazel D. Conjugative DNA transfer induces the bacterial SOS response and promotes antibiotic resistance development through integron activation. PLoS Genet. 2010; 6:e1001165.

[6] Beaber JW, Hochhut B, Waldor MK. SOS response promotes horizontal dissemination of antibiotic resistance genes. Nature. 2004; 427:72–74.

[7] Mitsuyama J, Yamada H, Maehana J, Fukuda Y, Kurose S, Minami S, et al. Characteristics of quinolone-induced small colony variants in Staphylococcus aureus. J Antimicrob Chemother. 1997; 39:697–705.

[8] Arias CA, Murray BE. Antibiotic-resistant bugs in the 21st century—a clinical super-challenge. N Engl J Med. 2009; 360:439–443.

[9] Tacconelli E, Carrara E, Savoldi A, Harbarth S, Mendelson M, Monnet DL, et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect Dis. 2018; 18:318–327.

[10] Chang W, Small DA, Toghrol F, Bentley WE. Global transcriptome analysis of Staphylococcus aureus response to hydrogen peroxide. J Bacteriol. 2006; 188:1648–1659.

[11] Wolf C, Hochgräfe F, Kusch H, Albrecht D, Hecker M, Engelmann S. Proteomic analysis of antioxidant strategies of Staphylococcus aureus: diverse responses to different oxidants. Proteomics. 2008; 8:3139–3153.

[12] Vestergaard M, Paulander W, Ingmer H. Activation of the SOS response increases the frequency of small colony variants. BMC Res Notes. 2015; 8:749.

[13] Hampton MB, Kettle AJ, Winterbourn CC. Involvement of superoxide and myeloperoxidase in oxygen-dependent killing of Staphylococcus aureus by neutrophils. Infect Immun. 1996; 64:3512–3517.

[14] Rigby KM, DeLeo FR. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol. 2012; 34:237–259.

[15] Peyrusson F, Varet H, Nguyen TK, Legendre R, Sismeiro O, Coppée JY, et al. Intracellular Staphylococcus aureus persisters upon antibiotic exposure. Nat Commun. 2020; 11:2200.

[16] Horvatek P, Salzer A, Hanna AMF, Gratani FL, Keinhörster D, Korn N, et al. Inducible expression of (pp)pGpp synthetases in Staphylococcus aureus is associated with activation of stress response genes. PLoS Genet. 2020; 16:e1009282.

[17] Kohanski MA, Dwyer DJ, Hayete B, Lawrence CA, Collins JJ. A common mechanism of cellular death induced by bactericidal antibiotics. Cell. 2007; 130:797–810.

[18] Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: from targets to networks. Nat Rev Microbiol. 2010; 8:423–435.

[19] Clarke RS, Ha KP, Edwards AM. RexAB promotes the survival of Staphylococcus aureus exposed to multiple classes of antibiotics. Antimicrob Agents Chemother. 2021; 65:e0059421.

[20] Clarke RS, Bruderer MS, Ha KP, Edwards AM. RexAB is essential for the mutagenic repair of Staphylococcus aureus DNA damage caused by co-trimoxazole. Antimicrob Agents Chemother. 2019; 63:e00944-19.

[21] Rosato RR, Fernandez R, Paz LI, Singh CR, Rosato AE. TCA cycle-mediated generation of ROS is a key mediator for HeR-MRSA survival under β-lactam antibiotic exposure. PLoS One. 2014; 9:e99605.

[22] Cirz RT, Jones MB, Gingles NA, Minogue TD, Jarrahi B, Peterson SN, et al. Complete and SOS-mediated response of Staphylococcus aureus to the antibiotic ciprofloxacin. J Bacteriol. 2007; 189:531–539.

[23] Fernandez R, Paz LI, Rosato RR, Rosato AE. Ceftaroline is active against heteroresistant methicillin-resistant Staphylococcus aureus clinical strains despite associated mutational mechanisms and intermediate levels of resistance. Antimicrob Agents Chemother. 2014; 58:5736–5746.

[24] Drlica K. Mechanism of fluoroquinolone action. Curr Opin Microbiol. 1999; 2:504–508.

[25] Gottschalk S, Ifrah D, Lerche S, Gottlieb CT, Cohn MT, Hiasa H, et al. The antimicrobial lysine-peptoid hybrid LP5 inhibits DNA replication and induces the SOS response in Staphylococcus aureus. BMC Microbiol. 2013; 13:192.

[26] Gottschalk S, Gottlieb CT, Vestergaard M, Hansen PR, Gram L, Ingmer H, et al. Amphibian antimicrobial peptide fallaxin analogue FL9 affects virulence gene expression and DNA replication in Staphylococcus aureus. J Med Microbiol. 2015; 64:1504–1513.

[27] Lueangsakulthai J, Jangpromma N, Temsiripong T, McKendrick JE, Khunkitti W, Maddocks SE, et al. A novel antibacterial peptide derived from crocodylus siamensis haemoglobin hydrolysate induces membrane permeabilization causing iron dysregulation, oxidative stress and bacterial death. J Appl Microbiol. 2017; 123:819–831.

[28] Auvray F, Perrat A, Arimizu Y, Chagneau CV, Bossuet-Greif N, Massip C, et al. Insights into the acquisition of the pks island and production of colibactin in the Escherichia coli population. Microb Genom. 2021; 7:000579.

[29] Silpe JE, Wong JWH, Owen SV, Baym M, Balskus EP. The bacterial toxin colibactin triggers prophage induction. Nature. 2022; 603:315–320.

[30] Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006; 444:337–342.

[31] Vestergaard M, Ingmer H. Antibacterial and antifungal properties of resveratrol. Int J Antimicro Ag. 2019; 53:716–723.

[32] Liu L, Ingmer H, Vestergaard M. Genome-wide identification of resveratrol intrinsic resistance determinants in Staphylococcus aureus. Antibiotics. 2021; 10:82.

[33] Cooper B, Islam N, Xu Y, Beard HS, Garrett WM, Gu G, et al. Quantitative proteomic analysis of Staphylococcus aureus treated with punicalagin, a natural antibiotic from pomegranate that disrupts iron homeostasis and induces SOS. Proteomics. 2018; 18:e1700461.

[34] Malone LM, Hampton HG, Morgan XC, Fineran PC. Type I CRISPR-Cas provides robust immunity but incomplete attenuation of phage-induced cellular stress. Nucleic Acids Res. 2022; 50:160–174.

[35] Dmytrenko O, Neumann GC, Hallmark T, Keiser DJ, Crowley VM, Vialetto E, et al. Cas12a2 elicits abortive infection through RNA-triggered destruction of dsDNA. Nature. 2023; 613:588–594.

[36] Mo CY, Mathai J, Rostøl JT, Varble A, Banh DV, Marraffini LA. Type III-A CRISPR immunity promotes mutagenesis of staphylococci. Nature. 2021; 592:611–615.

[37] Grosser MR, Paluscio E, Thurlow LR, Dillon MM, Cooper VS, Kawula TH, et al. Genetic requirements for Staphylococcus aureus nitric oxide resistance and virulence. PLoS Pathog. 2018; 14:e1006907.

[38] Kim GL, Hooven TA, Norambuena J, Li B, Boyd JM, Yang JH, et al. Growth and stress tolerance comprise independent metabolic strategies critical for Staphylococcus aureus infection. mBio. 2021; 12:e0081421.

[39] Painter KL, Strange E, Parkhill J, Bamford KB, Armstrong-James D, Edwards AM. Staphylococcus aureus adapts to oxidative stress by producing H₂O₂-resistant small-colony variants via the SOS response. Infect Immun. 2015; 83:1830–1844.

[40] Proctor RA, von Eiff C, Kahl BC, Becker K, McNamara P, Herrmann M, et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol. 2006; 4:295–305.

[41] Garzoni C, Kelley WL. Return of the trojan horse: intracellular phenotype switching and immune evasion by Staphylococcus aureus. EMBO Mol Med. 2011; 3:115–117.

[42] Haaber J, Penadés JR, Ingmer H. Transfer of antibiotic resistance in Staphylococcus aureus. TIM. 2017; 25:893–905.

[43] Maiques E, Úbeda C, Campoy S, Salvador N, Lasa I, Novick RP, et al. β-Lactam antibiotics induce the SOS response and horizontal transfer of virulence factors in Staphylococcus aureus. J Bacteriol. 2006; 188:2726–2729.

[44] Selva L, Viana D, Regev-Yochay G, Trzcinski K, Corpa JM, Lasa í, et al. Killing niche competitors by remote-control bacteriophage induction. Proc Natl Acad Sci USA. 2009; 106:1234–1238.

[45] Goerke C, Köller J, Wolz C. Ciprofloxacin and trimethoprim cause phage induction and virulence modulation in Staphylococcus aureus. Antimicrob Agents Chemother. 2006; 50:171–177.

[46] Thabet MA, Penadés JR, Haag AF. The ClpX protease is essential for inactivating the CI master repressor and completing prophage induction in Staphylococcus aureus. Nat Commun. 2023; 14:6599.

[47] Alibayov B, Baba-Moussa L, Sina H, Zdeňková K, Demnerová K. Staphylococcus aureus mobile genetic elements. Mol Biol Rep. 2014; 41:5005–5018.

[48] Morse ML. Transduction by staphylococcal bacteriophage. Proc Natl Acad Sci USA. 1959; 45:722–727.

[49] Ubeda C, Maiques E, Knecht E, Lasa I, Novick RP, Penadés JR, et al. Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci. Mol Microbiol. 2005; 56:836–844.

[50] Ruzin A, Lindsay J, Novick RP. Molecular genetics of SaPI1—a mobile pathogenicity island in Staphylococcus aureus. Mol Microbiol. 2001; 41:365–377.

[51] Chen J, Novick RP. Phage-mediated intergeneric transfer of toxin genes. Science. 2009; 323:139–141.

[52] Varga M, Kuntová L, Pantůček R, Mašlaňová I, Růžičková V, Doškař J. Efficient transfer of antibiotic resistance plasmids by transduction within methicillin-resistant Staphylococcus aureus USA300 clone. FEMS Microbiol Lett. 2012; 332:146–152.

[53] Scharn CR, Tenover FC, Goering RV. Transduction of staphylococcal cassette chromosome mec elements between strains of Staphylococcus aureus. Antimicrob Agents Chemother. 2013; 57:5233–5238.

[54] Savage VJ, Chopra I, O’Neill AJ. Staphylococcus aureus biofilms promote horizontal transfer of antibiotic resistance. Antimicrob Agents Chemother. 2013; 57:1968–1970.

[55] Bisognano C, Kelley WL, Estoppey T, Francois P, Schrenzel J, Li D, et al. A recA-LexA-dependent pathway mediates ciprofloxacin-induced fibronectin binding in Staphylococcus aureus. J Biol Chem. 2004; 279:9064–9071.

[56] Proctor RA, van Langevelde P, Kristjansson M, Maslow JN, Arbeit RD. Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus. Clin Infect Dis. 1995; 20:95–102.

[57] Massey RC, Buckling A, Peacock SJ. Phenotypic switching of antibiotic resistance circumvents permanent costs in Staphylococcus aureus. Curr Biol. 2001; 11:1810–1814.

[58] Tuchscherr L, Heitmann V, Hussain M, Viemann D, Roth J, von Eiff C, et al. Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence. J Infect Dis. 2010; 202:1031–1040.

[59] Schröder W, Goerke C, Wolz C. Opposing effects of aminocoumarins and fluoroquinolones on the SOS response and adaptability in Staphylococcus aureus. J Antimicrob Chemother. 2013; 68:529–538.

[60] Lin T, Pan J, Gregory C, Wang Y, Tincher C, Rivera C, et al. Contribution of the SOS response and the DNA repair systems to norfloxacin induced mutations in E. coli. Mar Life Sci Technol. 2023; 5:538–550.

[61] Keaton MA, Rosato RR, Plata KB, Singh CR, Rosato AE. Exposure of clinical MRSA heterogeneous strains to β-lactams redirects metabolism to optimize energy production through the TCA cycle. PLoS One. 2013; 8:e71025.

[62] Cuirolo A, Plata K, Rosato AE. Development of homogeneous expression of resistance in methicillin-resistant Staphylococcus aureus clinical strains is functionally associated with a β-lactam-mediated SOS response. J Antimicrob Chemother. 2009; 64:37–45.

[63] Tattevin P, Basuino L, Chambers HF. Subinhibitory fluoroquinolone exposure selects for reduced beta-lactam susceptibility in methicillin-resistant Staphylococcus aureus and alterations in the SOS-mediated response. Res Microbiol. 2009; 160:187–192.

[64] Bojer MS, Wacnik K, Kjelgaard P, Gallay C, Bottomley AL, Cohn MT, et al. SosA inhibits cell division in Staphylococcus aureus in response to DNA damage. Mol Microbiol. 2019; 112:1116–1130.

[65] Rapacka-Zdonczyk A, Wozniak A, Pieranski M, Woziwodzka A, Bielawski KP, Grinholc M. Development of Staphylococcus aureus tolerance to antimicrobial photodynamic inactivation and antimicrobial blue light upon sub-lethal treatment. Sci Rep. 2019; 9:9423.

[66] Little JW, Mount DW. The SOS regulatory system of Escherichia coli. Cell. 1982; 29:11–22.

[67] Erill I, Campoy S, Barbé J. Aeons of distress: an evolutionary perspective on the bacterial SOS response. FEMS Microbiol Rev. 2007; 31:637–656.

[68] Butala M, Žgur-Bertok D, Busby SJW. The bacterial LexA transcriptional repressor. Cell Mol Life Sci. 2009; 66:82–93.

[69] Chandran AV, Srikalaivani R, Paul A, Vijayan M. Biochemical characterization of Mycobacterium tuberculosis LexA and structural studies of its c-terminal segment. Acta Crystallogr D Struct Biol. 2019; 75:41–55.

[70] Luo Y, Pfuetzner RA, Mosimann S, Paetzel M, Frey EA, Cherney M, et al. Crystal structure of LexA: a conformational switch for regulation of self-cleavage. Cell. 2001; 106:585–594.

[71] Zhang AP, Pigli YZ, Rice PA. Structure of the LexA-DNA complex and implications for SOS box measurement. Nature. 2010; 466:883–886.

[72] Jaramillo AVC, Cory MB, Li A, Kohli RM, Wuest WM. Exploration of inhibitors of the bacterial LexA repressor-protease. Bioorg Med Chem Lett. 2022; 65:128702.

[73] Thliveris AT, Mount DW. Genetic identification of the DNA binding domain of Escherichia coli LexA protein. Proc Natl Acad Sci USA. 1992; 89:4500–4504.

[74] Cohn MT, Kjelgaard P, Frees D, Penadés JR, Ingmer H. Clp-dependent proteolysis of the LexA n-terminal domain in Staphylococcus aureus. Microbiology. 2011; 157:677–684.

[75] Frees D, Gerth U, Ingmer H. Clp chaperones and proteases are central in stress survival, virulence and antibiotic resistance of Staphylococcus aureus. IJMM. 2014; 304:142–149.

[76] Neher SB, Flynn JM, Sauer RT, Baker TA. Latent ClpX-recognition signals ensure LexA destruction after DNA damage. Genes Dev. 2003; 17:1084–1089.

[77] Mo CY, Culyba MJ, Selwood T, Kubiak JM, Hostetler ZM, Jurewicz AJ, et al. Inhibitors of LexA autoproteolysis and the bacterial SOS response discovered by an academic-industry partnership. ACS Infect Dis. 2018; 4:349–359.

[78] Selwood T, Larsen BJ, Mo CY, Culyba MJ, Hostetler ZM, Kohli RM, et al. Advancement of the 5-amino-1-(carbamoylmethyl)-1H-1,2,3-triazole-4-carboxamide scaffold to disarm the bacterial SOS response. Front Microbiol. 2018; 9:2961.

[79] Bellio P, Mancini A, Di Pietro L, Cracchiolo S, Franceschini N, Reale S, et al. Inhibition of the transcriptional repressor LexA: withstanding drug resistance by inhibiting the bacterial mechanisms of adaptation to antimicrobials. Life Sci. 2020; 241:117116.

[80] Caveney NA, Pavlin A, Caballero G, Bahun M, Hodnik V, de Castro L, et al. Structural insights into bacteriophage GIL01 gp7 inhibition of host LexA repressor. Structure. 2019; 27:1094–102.e4.

[81] Maso L, Vascon F, Chinellato M, Goormaghtigh F, Bellio P, Campagnaro E, et al. Nanobodies targeting LexA autocleavage disclose a novel suppression strategy of SOS-response pathway. Structure. 2022; 30:1479–93.e9.

[82] Little JW. Autodigestion of lexa and phage lambda repressors. Proc Natl Acad Sci USA. 1984; 81:1375–1379.

[83] Sassanfar M, Roberts JW. Nature of the SOS-inducing signal in Escherichia coli. J Mol Biol. 1990; 212:79–96.

[84] Bell JC, Kowalczykowski SC. RecA: regulation and mechanism of a molecular search engine. Trends Biochem Sci. 2016; 41:491–507.

[85] Chen Z, Yang H, Pavletich NP. Mechanism of homologous recombination from the RecA-ssDNA/dsDNA structures. Nature. 2008; 453:489–494.

[86] Gao B, Liang L, Su L, Wen A, Zhou C, Feng Y. Structural basis for regulation of SOS response in bacteria. Proc Natl Acad Sci USA. 2023; 120:e2217493120.

[87] Singh R, Ledesma KR, Chang KT, Tam VH. Impact of recA on levofloxacin exposure-related resistance development. Antimicrob Agents Chemother. 2010; 54:4262–4268.

[88] Mo CY, Manning SA, Roggiani M, Culyba MJ, Samuels AN, Sniegowski PD, et al. Systematically altering bacterial SOS activity under stress reveals therapeutic strategies for potentiating antibiotics. mSphere. 2016; 1:e00163-16.

[89] Lee AM, Ross CT, Zeng BB, Singleton SF. A molecular target for suppression of the evolution of antibiotic resistance: inhibition of the Escherichia coli RecA protein by N(6)-(1-naphthyl)-ADP. J Med Chem. 2005; 48:5408–5411.

[90] Wigle TJ, Singleton SF. Directed molecular screening for RecA ATPase inhibitors. Bioorg Med Chem Lett. 2007; 17:3249–3253.

[91] Nautiyal A, Patil KN, Muniyappa K. Suramin is a potent and selective inhibitor of Mycobacterium tuberculosis RecA protein and the SOS response: RecA as a potential target for antibacterial drug discovery. J Antimicrob Chemother. 2014; 69:1834–1843.

[92] Sexton JZ, Wigle TJ, He Q, Hughes MA, Smith GR, Singleton SF, et al. Novel inhibitors of E. coli RecA ATPase activity. Curr Chem Genomics. 2010; 4:34–42.

[93] Peterson EJR, Janzen WP, Kireev D, Singleton SF. High-throughput screening for RecA inhibitors using a transcreener adenosine 5′-O-diphosphate assay. Assay Drug Dev Technol. 2012; 10:260–268.

[94] Bellio P, Di Pietro L, Mancini A, Piovano M, Nicoletti M, Brisdelli F, et al. SOS response in bacteria: inhibitory activity of lichen secondary metabolites against Escherichia coli RecA protein. Phytomedicine. 2017; 29:11–18.

[95] Ojha D, Patil KN. p-Coumaric acid inhibits the Listeria monocytogenes RecA protein functions and SOS response: an antimicrobial target. Biochem Biophys Res Commun. 2019; 517:655–661.

[96] Kiran K, Patil KN. Gallic acid inhibits Staphylococcus aureus RecA protein functions: role in countering antibiotic resistance in bacteria. J Appl Microbiol. 2023; 135:lxad227.

[97] Alam MK, Alhhazmi A, DeCoteau JF, Luo Y, Geyer CR. RecA inhibitors potentiate antibiotic activity and block evolution of antibiotic resistance. Cell Chemical Biology. 2016; 23:381–391.

[98] Bunnell BE, Escobar JF, Bair KL, Sutton MD, Crane JK. Zinc blocks SOS-induced antibiotic resistance via inhibition of RecA in Escherichia coli. PLoS One. 2017; 12:e0178303.

[99] Noirot P, Gupta RC, Radding CM, Kolodner RD. Hallmarks of homology recognition by RecA-like recombinases are exhibited by the unrelated Escherichia coli RecT protein. EMBO J. 2003; 22:324–334.

[100] Cline DJ, Holt SL, Singleton SF. Inhibition of Escherichia coli RecA by rationally redesigned N-terminal helix. Org Biomol Chem. 2007; 5:1525–1528.

[101] Yakimov A, Pobegalov G, Bakhlanova I, Khodorkovskii M, Petukhov M, Baitin D. Blocking the RecA activity and SOS-response in bacteria with a short α-helical peptide. Nucleic Acids Res. 2017; 45:9788–9796.

[102] Petrova V, Chitteni-Pattu S, Drees JC, Inman RB, Cox MM. An SOS inhibitor that binds to free RecA protein: the PsiB protein. Mol Cell. 2009; 36:121–130.

[103] Yang J, Sun Y, Wang Y, Hao W, Cheng K. Structural and DNA end resection study of the bacterial NurA-HerA complex. BMC Biol. 2023; 21:42.

[104] Cheng K, Chen X, Xu G, Wang L, Xu H, Yang S, et al. Biochemical and functional characterization of the NurA–HerA complex from Deinococcus radiodurans. J Bacteriol. 2015; 197:2048–2061.

[105] Wigley DB. Bacterial DNA repair: recent insights into the mechanism of RecBCD, AddAB and AdnAB. Nat Rev Microbiol. 2013; 11:9–13.

[106] Cheng K, Wilkinson M, Chaban Y, Wigley DB. A conformational switch in response to Chi converts RecBCD from phage destruction to DNA repair. Nat Struct Mol Biol. 2020; 27:71–77.

[107] Krajewski WW, Fu X, Wilkinson M, Cronin NB, Dillingham MS, Wigley DB. Structural basis for translocation by AddAB helicase–nuclease and its arrest at χ sites. Nature. 2014; 508:416–419.

[108] Dziegielewska B, Beerman TA, Bianco PR. Inhibition of RecBCD enzyme by antineoplastic DNA alkylating agents. J Mol Biol. 2006; 361:898–919.

[109] Karu AE, Linn S. Uncoupling of the recBC ATPase from DNase by DNA crosslinked with psoralen. Proc Natl Acad Sci USA. 1972; 69:2855–2859.

[110] Sun D, Hurley LH. Structure-activity relationships of (+)-CC-1065 analogues in the inhibition of helicase-catalyzed unwinding of duplex DNA. J Med Chem. 1992; 35:1773–1782.

[111] Amundsen SK, Spicer T, Karabulut AC, Londoño LM, Eberhart C, Fernandez Vega V, et al. Small-molecule inhibitors of bacterial AddAB and RecBCD helicase-nuclease DNA repair enzymes. ACS Chem Biol. 2012; 7:879–891.

[112] Wilkinson M, Troman LA, Wan Nur Ismah WA, Chaban Y, Avison MB, Dillingham MS, et al. Structural basis for the inhibition of RecBCD by Gam and its synergistic antibacterial effect with quinolones. eLife. 2016; 5:e22963.

[113] Wilkinson M, Wilkinson OJ, Feyerherm C, Fletcher EE, Wigley DB, Dillingham MS. Structures of RecBCD in complex with phage-encoded inhibitor proteins reveal distinctive strategies for evasion of a bacterial immunity hub. eLife. 2022; 11:e83409.

[114] Cromie GA. Phylogenetic ubiquity and shuffling of the bacterial RecBCD and AddAB recombination complexes. J Bacteriol. 2009; 191:5076–5084.

[115] Chédin F, Noirot P, Biaudet V, Ehrlich SD. A five-nucleotide sequence protects DNA from exonucleolytic degradation by AddAB, the RecBCD analogue of Bacillus subtilis. Mol Microbiol. 1998; 29:1369–1377.

[116] Halpern D, Chiapello H, Schbath S, Robin S, Hennequet-Antier C, Gruss A, et al. Identification of DNA motifs implicated in maintenance of bacterial core genomes by predictive modeling. PLoS Genet. 2007; 3:1614–21.

[117] Shinn MK, Chaturvedi SK, Kozlov AG, Lohman TM. Allosteric effects of E. coli SSB and RecR proteins on RecO protein binding to DNA. Nucleic Acids Res. 2023; 51:2284–2297.

[118] Cheng K, Xu H, Chen X, Wang L, Tian B, Zhao Y, et al. Structural basis for DNA 5′-end resection by RecJ. eLife. 2016; 5:e14294.

[119] Morimatsu K, Kowalczykowski SC. RecQ helicase and RecJ nuclease provide complementary functions to resect DNA for homologous recombination. Proc Natl Acad Sci USA. 2014; 111: E5133–E5142.

[120] Cheng K, Xu Y, Chen X, Lu H, He Y, Wang L, et al. Participation of RecJ in the base excision repair pathway of Deinococcus radiodurans. Nucleic Acids Res. 2020; 48:9859–9871.

[121] Huang YH, Guan HH, Chen CJ, Huang CY. Staphylococcus aureus single-stranded DNA-binding protein SsbA can bind but cannot stimulate PriA helicase. PLoS One. 2017; 12:e0182060.

[122] Lin ES, Huang CY. Crystal structure of the single-stranded DNA-binding protein SsbB in complex with the anticancer drug 5-fluorouracil: extension of the 5-fluorouracil interactome to include the oligonucleotide/oligosaccharide-binding fold protein. Biochem Biophys Res Commun. 2021; 534:41–46.

[123] Huang YH, Huang CY. SAAV2152 is a single-stranded DNA binding protein: the third SSB in Staphylococcus aureus. Oncotarget. 2018; 9:20239–20254.

[124] Huang CY. Crystal structure of SSB complexed with inhibitor myricetin. Biochem Biophys Res Commun. 2018; 504:704–708.

[125] Voter AF, Killoran MP, Ananiev GE, Wildman SA, Hoffmann FM, Keck JL. A High-throughput screening strategy to identify inhibitors of SSB protein-protein interactions in an academic screening facility. SLAS Discov. 2018; 23:94–101.

[126] Chilingaryan Z, Headey SJ, Lo ATY, Xu ZQ, Otting G, Dixon NE, et al. Fragment-based discovery of inhibitors of the bacterial DnaG-SSB interaction. Antibiotics. 2018; 7:14.

[127] Mazloum N, Stegman MA, Croteau DL, Van Houten B, Kwon NS, Ling Y, et al. Identification of a chemical that inhibits the mycobacterial UvrABC complex in nucleotide excision repair. Biochemistry. 2011; 50:1329–1335.

[128] Pommier Y, Marchand C. Interfacial inhibitors: targeting macromolecular complexes. Nat Rev Drug Discov. 2011; 11:25–36.

[129] Kolarič A, Anderluh M, Minovski N. Two decades of successful SAR-grounded stories of the novel bacterial topoisomerase inhibitors (NBTIs). J Med Chem. 2020; 63:5664–5674.

[130] Kokot M, Anderluh M, Hrast M, Minovski N. The structural features of novel bacterial topoisomerase inhibitors that define their activity on topoisomerase IV. J Med Chem. 2022; 65:6431–6440.

[131] Phillips JW, Goetz MA, Smith SK, Zink DL, Polishook J, Onishi R, et al. Discovery of kibdelomycin, a potent new class of bacterial type II topoisomerase inhibitor by chemical-genetic profiling in Staphylococcus aureus. Chem Biol. 2011; 18:955–965.

[132] Lu CH, McCloskey A, Chen FR, Nakayasu ES, Zhang LQ, Luo ZQ. Fic proteins inhibit the activity of topoisomerase IV by AMPylation in diverse bacteria. Front Microbiol. 2020; 11:2084.

[133] Janion C. Inducible SOS response system of DNA repair and mutagenesis in Escherichia coli. Int J Biol Sci. 2008; 4:338–344.

[134] Glanzer JG, Endres JL, Byrne BM, Liu S, Bayles KW, Oakley GG. Identification of inhibitors for single-stranded DNA-binding proteins in eubacteria. J Antimicrob Chemother. 2016; 71:3432–3440.

[135] Shereda RD, Kozlov AG, Lohman TM, Cox MM, Keck JL. SSB as an organizer/mobilizer of genome maintenance complexes. Crit Rev Biochem Mol Biol. 2008; 43:289–318.

[136] Attaiech L, Olivier A, Mortier-Barriere I, Soulet AL, Granadel C, Martin B, et al. Role of the single-stranded DNA-binding protein SsbB in pneumococcal transformation: maintenance of a reservoir for genetic plasticity. PLoS Genet. 2011; 7:e1002156.

[137] Manthei KA, Hill MC, Burke JE, Butcher SE, Keck JL. Structural mechanisms of DNA binding and unwinding in bacterial RecQ helicases. Proc Natl Acad Sci USA. 2015; 112:4292–4297.

[138] Iguchi S, Mizutani T, Hiramatsu K, Kikuchi K. Rapid acquisition of linezolid resistance in methicillin-resistant Staphylococcus aureus: role of hypermutation and homologous recombination. PLoS One. 2016; 11:e0155512.

[139] Ledger EVK, Lau K, Tate EW, Edwards AM. XerC is required for the repair of antibiotic- and immune-mediated DNA damage in Staphylococcus aureus. Antimicrob Agents Chemother. 2023; 67:e0120622.

[140] Poleszak K, Kaminska KH, Dunin-Horkawicz S, Lupas A, Skowronek KJ, Bujnicki JM. Delineation of structural domains and identification of functionally important residues in DNA repair enzyme exonuclease VII. Nucleic Acids Res. 2012; 40:8163–8174.

[141] Sirois S, Szatmari G. Detection of XerC and XerD recombinases in gram-negative bacteria of the family Enterobacteriaceae. J Bacteriol. 1995; 177:4183–4186.

[142] Michel B, Sinha AK, Leach DRF. Replication fork breakage and restart in Escherichia coli. Microbiol Mol Biol Rev. 2018; 82:e00013-8.

[143] Sancar A. DNA excision repair. Annu Rev Biochem. 1996; 65:43–81.

[144] Gulbis JM, Zhou M, Mann S, MacKinnon R. Structure of the cytoplasmic beta subunit-T1 assembly of voltage-dependent K⁺ channels. Science. 2000; 289:123–127.

[145] Usongo V, Drolet M. Roles of type 1A topoisomerases in genome maintenance in Escherichia coli. PLoS Genet. 2014; 10:e1004543.

[146] Úbeda C, Maiques E, Tormo MÁ, Campoy S, Lasa Í, Barbé J, et al. SaPI operon I is required for SaPI packaging and is controlled by LexA. Mol Microbiol. 2007; 65:41–50.

[147] Pakotiprapha D, Samuels M, Shen K, Hu JH, Jeruzalmi D. Structure and mechanism of the UvrA-UvrB DNA damage sensor. Nat Struct Mol Biol. 2012; 19:291–298.

[148] Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001; 70:369–413.

[149] Barrett TC, Mok WWK, Murawski AM, Brynildsen MP. Enhanced antibiotic resistance development from fluoroquinolone persisters after a single exposure to antibiotic. Nat Commun. 2019; 10:1177.

[150] Savage VJ, Charrier C, Salisbury AM, Moyo E, Forward H, Chaffer-Malam N, et al. Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV. J Antimicrob Chemother. 2016; 71:1905–1913.

[151] Morgan H, Lipka-Lloyd M, Warren AJ, Hughes N, Holmes J, Burton NP, et al. A 2.8 Å structure of zoliflodacin in a DNA cleavage complex with Staphylococcus aureus DNA gyrase. Int J Mol Sci. 2023; 24:1634.

[152] Grossman S, Fishwick CWG, McPhillie MJ. Developments in non-intercalating bacterial topoisomerase inhibitors: allosteric and ATPase inhibitors of DNA gyrase and topoisomerase IV. Pharmaceuticals. 2023; 16:261.

[153] Lu J, Patel S, Sharma N, Soisson SM, Kishii R, Takei M, et al. Structures of kibdelomycin bound to Staphylococcus aureus GyrB and ParE showed a novel U-shaped binding mode. ACS Chem Biol. 2014; 9:2023–2031.

[154] Stracker TH, Petrini JH. The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol. 2011; 12:90–103.

[155] Käshammer L, Saathoff JH, Lammens K, Gut F, Bartho J, Alt A, et al. Mechanism of DNA end sensing and processing by the Mre11-Rad50 complex. Mol Cell. 2019; 76:382-94 e6.

[156] Lee J, Jo I, Ahn J, Hong S, Jeong S, Kwon A, et al. Crystal structure of the nuclease and capping domain of SbcD from Staphylococcus aureus. J Microbiol. 2021; 59:584–589.

[157] Courcelle J, Khodursky A, Peter B, Brown PO, Hanawalt PC. Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli. Genetics. 2001; 158:41–64.

[158] Reuven NB, Arad G, Maor-Shoshani A, Livneh Z. The mutagenesis protein UmuC is a DNA polymerase activated by UmuD′, RecA, and SSB and is specialized for translesion replication. J Biol Chem. 1999; 274:31763–31766.

[159] Watson SP, Antonio M, Foster SJ. Isolation and characterization of Staphylococcus aureus starvat ion4 nduced, stationary-phase mutants defective in survival or recovery. Microbiology. 1998; 144:3159–3169.

[160] Sutton MD, Smith BT, Godoy VG, Walker GC. The SOS response: recent insights into umuDC-dependent mutagenesis and DNA damage tolerance. Annu Rev Genet. 2000; 34:479–497.

[161] Permina EA, Mironov AA, Gelfand MS. Damage-repair error-prone polymerases of eubacteria: association with mobile genome elements. Gene. 2002; 293:133–140.

[162] Peat TS, Frank EG, McDonald JP, Levine AS, Woodgate R, Hendrickson WA. Structure of the UmuD′ protein and its regulation in response to DNA damage. Nature. 1996; 380:727–730.

[163] Gonzalez M, Woodgate R. The “tale” of UmuD and its role in SOS mutagenesis. BioEssays. 2002; 24:141–148.

[164] Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017; 58:235–263.

[165] Zhang Y, Lin K. A phylogenomic analysis of Escherichia coli/shigella group: implications of genomic features associated with pathogenicity and ecological adaptation. BMC Evol Biol. 2012; 12:174.

[166] Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009; 325:1089–1093.

[167] Palmer AC, Kishony R. Understanding, predicting and manipulating the genotypic evolution of antibiotic resistance. Nat Rev Genet. 2013; 14:243–248.

[168] Yakimov A, Bakhlanova I, Baitin D. Targeting evolution of antibiotic resistance by SOS response inhibition. Comput Struct Biotechnol J. 2021; 19:777–783.

[169] Uhlemann AC, Otto M, Lowy FD, DeLeo FR. Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus. Infect Genet Evol. 2014; 21:563–574.

[170] Jernberg C, Löfmark S, Edlund C, Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010; 156:3216–3223.

[171] Peng Q, Zhou S, Yao F, Hou B, Huang Y, Hua D, et al. Baicalein suppresses the SOS response system of Staphylococcus aureus induced by ciprofloxacin. Cell Physiol Biochem. 2011; 28:1045–1050.

[172] Liu Z, Shen Z, Xiang S, Sun Y, Cui J, Jia J. Evaluation of 1,4-naphthoquinone derivatives as antibacterial agents: activity and mechanistic studies. Front Environ Sci Eng. 2023; 17:31.

[173] Carvalho Junior AR, Martins ALB, Cutrim BS, Santos DM, Maia HS, Silva MSM, et al. Betulinic acid prevents the acquisition of ciprofloxacin-mediated mutagenesis in Staphylococcus aureus. Molecules. 2019; 24:1757.

[174] Bulssico J, PapukashvilI I, Espinosa L, Gandon S, Ansaldi M. Phage-antibiotic synergy: cell filamentation is a key driver of successful phage predation. PLoS Pathog. 2023; 19:e1011602.

RIGHTS & PERMISSIONS

2024 The Author(s). mLife published by John Wiley & Sons Australia, Ltd on behalf of Institute of Microbiology, Chinese Academy of Sciences.