Research progress in adaptive survival and pathogenic mechanisms of toxin-antitoxin systems in Staphylococcus aureus

doi:10.3969/j.issn.1674-8115.2026.07.002

Abstract

Abstract:

Toxin-antitoxin systems (TAS) are widely distributed in bacteria and archaea, typically consisting of a toxin that inhibits bacterial growth and a cognate antitoxin that neutralizes its toxicity. These systems have been recognized as key regulators of bacterial growth, metabolism, and pathogenesis. Staphylococcus aureus (S. aureus) is an important clinical pathogen that can cause a wide range of diseases, ranging from skin and soft tissue infections to sepsis and endocarditis. Studies have shown that TAS play important roles in stress resistance, persister cell formation, and biofilm development in S. aureus. Elucidating the underlying molecular mechanisms is essential for understanding the pathogenic characteristics of S. aureus and for developing novel antibacterial strategies. Here, This review summarizes the classification and structural features of TAS in S. aureus and discuss their functions in adaptive survival and virulence regulation. It focuses on how, under nutrient limitation or antibiotic pressure, TAS interfere with DNA replication and protein synthesis to induce a metabolically dormant state, thereby contributing to phenotypic tolerance and persister cell formation. This review further describes how TAS modulate virulence factor expression through global regulatory networks and how certain TAS-encoded toxins directly damage eukaryotic membranes to promote bacterial invasion and dissemination. Additionally, it highlights the contribution of the type Ⅶ secretion system to toxin export, which provides a competitive advantage to S. aureus within polymicrobial communities. This review systematically summarizes the structural characteristics and functional modes of different types of TAS in S. aureus, aiming to deepen the understanding of its pathogenic mechanisms and to provide theoretical references and research directions for the development of novel TAS-targeted antibacterial strategies.

Key words: Staphylococcus aureus, toxin-antitoxin system, persister cell, biofilm, pathogenicity

CLC Number:

R378.11

Xie Xinni, Lü Yan, Li Min, Wang Yanan. Research progress in adaptive survival and pathogenic mechanisms of toxin-antitoxin systems in Staphylococcus aureus[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(7): 839-846.

Figures/Tables 3

TrendMD

References 57

[1]	Tong S Y C, Davis J S, Eichenberger E, et al. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management[J]. Clin Microbiol Rev, 2015, 28(3): 603-661.
[2]	Hassoun A, Linden P K, Friedman B. Incidence, prevalence, and management of MRSA bacteremia across patient populations: a review of recent developments in MRSA management and treatment[J]. Crit Care, 2017, 21(1): 211.
[3]	Selim S, Faried O A, Almuhayawi M S, et al. Incidence of vancomycin-resistant Staphylococcus aureus strains among patients with urinary tract infections[J]. Antibiotics (Basel), 2022, 11(3): 408.
[4]	Zhou S, Zhou K, Yang P H, et al. Molecular characteristics and antimicrobial resistance of linezolid-resistant Staphylococcus aureus in osteoarticular infections: a 11-year study from a hospital in Xi′an[J]. Infect Drug Resist, 2025, 18: 2987-2996.
[5]	Harms A, Brodersen D E, Mitarai N, et al. Toxins, targets, and triggers: an overview of toxin-antitoxin biology[J]. Mol Cell, 2018, 70(5): 768-784.
[6]	Unterholzner S J, Poppenberger B, Rozhon W. Toxin-antitoxin systems: biology, identification, and application[J]. Mob Genet Elements, 2013, 3(5): e26219.
[7]	van Gundy T, Martin E, Bono J, et al. An antisense RNA fine-tunes gene expression of the type Ⅱ MazEF toxin-antitoxin system[J]. mBio, 2022, 13(1): e0344321.
[8]	Karimaei S, Kazem Aghamir S M, Foroushani A R, et al. Antibiotic tolerance in biofilm persister cells of Staphylococcus aureus and expression of toxin-antitoxin system genes[J]. Microb Pathog, 2021, 159: 105126.
[9]	Bukowski M, Banasik M, Chlebicka K, et al. Analysis of co-occurrence of type Ⅱ toxin-antitoxin systems and antibiotic resistance determinants in Staphylococcus aureus[J]. mSystems, 2025, 10(3): e0095724.
[10]	Karimaei S, Kalani B S, Shahrokhi N, et al. Expression of type Ⅱ toxin-antitoxin systems and ClpP protease of methicillin-resistant Staphylococcus aureus under thermal and oxidative stress conditions[J]. Iran J Microbiol, 2021, 13(2): 204-211.
[11]	Peacock S J, Moore C E, Justice A, et al. Virulent combinations of adhesin and toxin genes in natural populations of Staphylococcus aureus[J]. Infect Immun, 2002, 70(9): 4987-4996.
[12]	Archer N K, Mazaitis M J, Costerton J W, et al. Staphylococcus aureus biofilms: properties, regulation, and roles in human disease[J]. Virulence, 2011, 2(5): 445-459.
[13]	Gerdes K, Rasmussen P B, Molin S. Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells[J]. Proc Natl Acad Sci U S A, 1986, 83(10): 3116-3120.
[14]	Ogura T, Hiraga S. Mini-F plasmid genes that couple host cell division to plasmid proliferation[J]. Proc Natl Acad Sci U S A, 1983, 80(15): 4784-4788.
[15]	Steif A, Meyer I M. The hok mRNA family[J]. RNA Biol, 2012, 9(12): 1399-1404.
[16]	Pandey D P, Gerdes K. Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes[J]. Nucleic Acids Res, 2005, 33(3): 966-976.
[17]	Jurėnas D, Fraikin N, Goormaghtigh F, et al. Biology and evolution of bacterial toxin-antitoxin systems[J]. Nat Rev Microbiol, 2022, 20(6): 335-350.
[18]	Chlebicka K, Bonar E, Suder P, et al. Impacts of the type Ⅰ toxin-antitoxin system, SprG1/SprF1, on Staphylococcus aureus gene expression[J]. Genes, 2021, 12(5): 770.
[19]	Fermon L, Germain-Amiot N, Oriol C, et al. Membrane selectivity and pore formation of SprA1 and SprA2 hemolytic peptides from Staphylococcus aureus type Ⅰ toxin-antitoxin systems[J]. FEBS J, 2025, 292(17): 4555-4579.
[20]	Mandell J B, Gish C, Cappellini A J, et al. Methicillin resistant Staphylococcus aureus mazEF expression promotes infections by influencing cellular growth, antibiotic sensitivity, and formation of biofilms[J]. Sci Rep, 2024, 14(1): 21269.
[21]	Xue L, Khan M H, Yue J, et al. The two paralogous copies of the YoeB-YefM toxin-antitoxin module in Staphylococcus aureus differ in DNA binding and recognition patterns[J]. J Biol Chem, 2022, 298(1): 101457.
[22]	Habib G, Zhu Q, Sun B L. Bioinformatics and functional assessment of toxin-antitoxin systems in Staphylococcus aureus[J]. Toxins, 2018, 10(11): 473.
[23]	Short F L, Pei X Y, Blower T R, et al. Selectivity and self-assembly in the control of a bacterial toxin by an antitoxic noncoding RNA pseudoknot[J]. Proc Natl Acad Sci U S A, 2013, 110(3): E241-E249.
[24]	Blower T R, Short F L, Rao F, et al. Identification and classification of bacterial type Ⅲ toxin-antitoxin systems encoded in chromosomal and plasmid genomes[J]. Nucleic Acids Res, 2012, 40(13): 6158-6173.
[25]	Nadig K, Sandhya S, Singh M. Bioinformatic exploration reveals features of tenpIN family of type Ⅲ toxin-antitoxin systems in bacteria and viruses[J]. Sci Rep, 2025, 15(1): 26624.
[26]	Goeders N, Chai R, Chen B H, et al. Structure, evolution, and functions of bacterial type Ⅲ toxin-antitoxin systems[J]. Toxins, 2016, 8(10): 282.
[27]	Lechner S, Lewis K, Bertram R. Staphylococcus aureus persisters tolerant to bactericidal antibiotics[J]. J Mol Microbiol Biotechnol, 2012, 22(4): 235-244.
[28]	Keren I, Shah D, Spoering A, et al. Specialized persister cells and the mechanism of multidrug tolerance in Escherichia Coli[J]. J Bacteriol, 2004, 186(24): 8172-8180.
[29]	Pinel-Marie M L, Brielle R, Riffaud C, et al. RNA antitoxin SprF1 binds ribosomes to attenuate translation and promote persister cell formation in Staphylococcus aureus[J]. Nat Microbiol, 2021, 6(2): 209-220.
[30]	Habib G, Zhu J D, Sun B L. A novel type Ⅰ toxin-antitoxin system modulates persister cell formation in Staphylococcus aureus[J]. Int J Med Microbiol, 2020, 310(2): 151400.
[31]	Wang X X, Lord D M, Cheng H Y, et al. A new type Ⅴ toxin-antitoxin system where mRNA for toxin GhoT is cleaved by antitoxin GhoS[J]. Nat Chem Biol, 2012, 8(10): 855-861.
[32]	Kwan B W, Valenta J A, Benedik M J, et al. Arrested protein synthesis increases persister-like cell formation[J]. Antimicrob Agents Chemother, 2013, 57(3): 1468-1473.
[33]	Ma D Z, Mandell J B, Donegan N P, et al. The toxin-antitoxin MazEF drives Staphylococcus aureus biofilm formation, antibiotic tolerance, and chronic infection[J]. mBio, 2019, 10(6): e01658-e01619.
[34]	Qi X Y, Brothers K M, Ma D Z, et al. The Staphylococcus aureus toxin-antitoxin system YefM-YoeB is associated with antibiotic tolerance and extracellular dependent biofilm formation[J]. J Bone Jt Infect, 2021, 6(7): 241-253.
[35]	Tripathi A, Dewan P C, Ahmed S, et al. MazF-induced growth inhibition and persister generation in Escherichia Coli[J]. J Biol Chem, 2014, 289(7): 4191-4205.
[36]	Fluckiger U, Ulrich M, Steinhuber A, et al. Biofilm formation, icaADBC transcription, and polysaccharide intercellular adhesin synthesis by staphylococci in a device-related infection model[J]. Infect Immun, 2005, 73(3): 1811-1819.
[37]	Ma D M, Gu H J, Shi Y J, et al. Edwardsiella piscicida YefM-YoeB: a type Ⅱ toxin-antitoxin system that is related to antibiotic resistance, biofilm formation, serum survival, and host infection[J]. Front Microbiol, 2021, 12: 646299.
[38]	Wen W, Liu B H, Xue L, et al. Autoregulation and virulence control by the toxin-antitoxin system SavRS in Staphylococcus aureus[J]. Infect Immun, 2018, 86(5): e00032-e00018.
[39]	Sierra R, Prados J, Panasenko O O, et al. Insights into the global effect on Staphylococcus aureus growth arrest by induction of the endoribonuclease MazF toxin[J]. Nucleic Acids Res, 2020, 48(15): 8545-8561.
[40]	Bezrukov F, Prados J, Renzoni A, et al. MazF toxin causes alterations in Staphylococcus aureus transcriptome, translatome and proteome that underlie bacterial dormancy[J]. Nucleic Acids Res, 2021, 49(4): 2085-2101.
[41]	Germain-Amiot N, Augagneur Y, Camberlein E, et al. A novel Staphylococcus aureus cis-trans type Ⅰ toxin-antitoxin module with dual effects on bacteria and host cells[J]. Nucleic Acids Res, 2019, 47(4): 1759-1773.
[42]	Chaudhary K, Kumar R, Singh S, et al. A web server and mobile app for computing hemolytic potency of peptides[J]. Sci Rep, 2016, 6: 22843.
[43]	Chen Y X, Guarnieri M T, Vasil A I, et al. Role of peptide hydrophobicity in the mechanism of action of α-helical antimicrobial peptides[J]. Antimicrob Agents Chemother, 2007, 51(4): 1398-1406.
[44]	Hancock R E W, Rozek A. Role of membranes in the activities of antimicrobial cationic peptides[J]. FEMS Microbiol Lett, 2002, 206(2): 143-149.
[45]	Ravn P, Arnau J, Madsen S M, et al. Optimization of signal peptide SP310 for heterologous protein production in Lactococcus lactis[J]. Microbiology (Reading), 2003, 149(Pt 8): 2193-2201.
[46]	Pinel-Marie M L, Brielle R, Felden B. Dual toxic-peptide-coding Staphylococcus aureus RNA under antisense regulation targets host cells and bacterial rivals unequally[J]. Cell Rep, 2014, 7(2): 424-435.
[47]	Fermon L, Burel A, Ostyn E, et al. Mechanism of action of sprG1-encoded type Ⅰ toxins in Staphylococcus aureus: from membrane alterations to mesosome-like structures formation and bacterial lysis[J]. Front Microbiol, 2023, 14: 1275849.
[48]	Kato F, Bandou, Yamaguchi Y, et al. Characterization of a membrane toxin-antitoxin system, tsaAT, from Staphylococcus aureus[J]. FEBS J, 2024, 291(22): 5015-5036.
[49]	Cao Z P, Casabona M G, Kneuper H, et al. The type Ⅶ secretion system of Staphylococcus aureus secretes a nuclease toxin that targets competitor bacteria[J]. Nat Microbiol, 2016, 2: 16183.
[50]	Kato F, Yoshizumi S, Yamaguchi Y, et al. Genome-wide screening for identification of novel toxin-antitoxin systems in Staphylococcus aureus[J]. Appl Environ Microbiol, 2019, 85(20): e00915-e00919.
[51]	Warne B, Harkins C P, Harris S R, et al. The Ess/Type Ⅶ secretion system of Staphylococcus aureus shows unexpected genetic diversity[J]. BMC Genomics, 2016, 17: 222.
[52]	Williams J J, Hergenrother P J. Artificial activation of toxin-antitoxin systems as an antibacterial strategy[J]. Trends Microbiol, 2012, 20(6): 291-298.
[53]	Lee H T, Kim S K, Lee J B, et al. A novel peptide nucleic acid against the cytidine monophosphate kinase of S. aureus inhibits staphylococcal infection in vivo[J]. Mol Ther Nucleic Acids, 2019, 18: 245-252.
[54]	Luo F M, Xu C F, Zhang C W, et al. mRNA-based platform for preventing and treating Staphylococcus aureus by targeted staphylococcal enterotoxin B[J]. Front Immunol, 2024, 15: 1490044.
[55]	Xu W F, Yan P, Li Y J, et al. The toxin-antitoxin system SavRS contributes to vancomycin resistance in vancomycin-intermediate Staphylococcus aureus by mediating cell wall thickening[J]. J Antimicrob Chemother, 2025, 80(11): 2978-2988.
[56]	Sæbø I P,Dyhr E,Riisnæs I M M, et al. Rational design of synthetic antimicrobial peptides based on the Escherichia Coli ShoB toxin[J]. Sci Rep, 2025, 15(1): 14354.
[57]	Chen Z, Yao J Y, Zhang P J, et al. Minimized antibiotic-free plasmid vector for gene therapy utilizing a new toxin-antitoxin system[J]. Metab Eng, 2023, 79: 86-96.

Type	Toxin	Antitoxin	Characteristic	Representative TAS in S. aureus
Ⅰ	mRNA	Antisense RNA	The toxin is a small peptide encoded by an mRNA. A complementary antisense RNA antitoxin inhibits toxin translation through base pairing	sprG1/sprF1^[18], sprA1/sprA2^[19]
Ⅱ	Protein	Protein	Both toxin and antitoxin are proteins. The antitoxin neutralizes the toxin through direct protein-protein interaction	MazEF^[20], YefM-YoeB^[21], HigBA^[22]
Ⅲ	Protein	RNA	A protein toxin is inactivated by an RNA antitoxin that binds to it, inducing conformational inactivation ^[23]	TenpIN^[24]
Ⅳ	Protein	Protein	The protein antitoxin inhibits the toxin indirectly by blocking its interaction with the cellular target rather than by direct binding	Not reported
Ⅴ	Protein	Protein	The antitoxin acts as an RNase that specifically cleaves the toxin mRNA, thereby preventing toxin synthesis	Not reported
Ⅵ	Protein	Protein	The antitoxin promotes protease-mediated degradation of the toxin protein through direct interaction	Not reported
Ⅶ	Protein	Protein	The antitoxin inactivates the toxin by facilitating its post-translational modification	Not reported
Ⅷ	RNA	RNA	An RNA antitoxin inhibits either transcription of the toxin gene or neutralizes the toxin RNA through direct binding	Not reported

Type	Toxin	Antitoxin	Characteristic	Representative TAS in S. aureus
Ⅰ	mRNA	Antisense RNA	The toxin is a small peptide encoded by an mRNA. A complementary antisense RNA antitoxin inhibits toxin translation through base pairing	sprG1/sprF1^[18], sprA1/sprA2^[19]
Ⅱ	Protein	Protein	Both toxin and antitoxin are proteins. The antitoxin neutralizes the toxin through direct protein-protein interaction	MazEF^[20], YefM-YoeB^[21], HigBA^[22]
Ⅲ	Protein	RNA	A protein toxin is inactivated by an RNA antitoxin that binds to it, inducing conformational inactivation ^[23]	TenpIN^[24]
Ⅳ	Protein	Protein	The protein antitoxin inhibits the toxin indirectly by blocking its interaction with the cellular target rather than by direct binding	Not reported
Ⅴ	Protein	Protein	The antitoxin acts as an RNase that specifically cleaves the toxin mRNA, thereby preventing toxin synthesis	Not reported
Ⅵ	Protein	Protein	The antitoxin promotes protease-mediated degradation of the toxin protein through direct interaction	Not reported
Ⅶ	Protein	Protein	The antitoxin inactivates the toxin by facilitating its post-translational modification	Not reported
Ⅷ	RNA	RNA	An RNA antitoxin inhibits either transcription of the toxin gene or neutralizes the toxin RNA through direct binding	Not reported