1887

Microbiology Society logo

Volume 166, Issue 11

The general stress response of promotes tolerance of antibiotics and survival in whole human blood Open Access

Abstract

is a frequent cause of invasive human infections such as bacteraemia and infective endocarditis. These infections frequently relapse or become chronic, suggesting that the pathogen has mechanisms to tolerate the twin threats of therapeutic antibiotics and host immunity. The general stress response of is regulated by the alternative sigma factor B (σB) and provides protection from multiple stresses including oxidative, acidic and heat. σB also contributes to virulence, intracellular persistence and chronic infection. However, the protective effect of σB on bacterial survival during exposure to antibiotics or host immune defences is poorly characterized. We found that σB promotes the survival of exposed to the antibiotics gentamicin, ciprofloxacin, vancomycin and daptomycin, but not oxacillin or clindamycin. We also found that σB promoted staphylococcal survival in whole human blood, most likely via its contribution to oxidative stress resistance. Therefore, we conclude that the general stress response of may contribute to the development of chronic infection by conferring tolerance to both antibiotics and host immune defences.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): antibiotics , SigB , sigma factor , Staphylococcus aureus and tolerance
Funding
This study was supported by the:
  • Medical Research Council (Award MR/J006874/1)
    • Principle Award Recipient: Not Applicable
  • National Institute for Health Research
    • Principle Award Recipient: Not Applicable
© 2020 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000983
2020-10-23
2024-04-26
Loading full text...

Full text loading...

/deliver/fulltext/micro/166/11/1088.html?itemId=/content/journal/micro/10.1099/mic.0.000983&mimeType=html&fmt=ahah

References

  1. Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998; 339:520–532 [View Article][PubMed]
     [Google Scholar]
  2. Gordon RJ, Lowy FD. Pathogenesis of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 2008; 46:S350–S359 [View Article][PubMed]
     [Google Scholar]
  3. Chen C-J, Su L-H, Lin T-Y, Huang Y-C. Molecular analysis of repeated methicillin-resistant Staphylococcus aureus infections in children. PLoS One 2010; 5:e14431 [View Article][PubMed]
     [Google Scholar]
  4. Peyrani P, Allen M, Seligson D, Roberts C, Chen A et al. Clinical outcomes of osteomyelitis patients infected with methicillin-resistant Staphylococcus aureus USA-300 strains. Am J Orthop 2012; 41:117–122[PubMed]
     [Google Scholar]
  5. Fowler VG, Sakoulas G, McIntyre LM, Meka VG, Arbeit RD et al. Persistent bacteremia due to methicillin-resistant Staphylococcus aureus infection is associated with agr dysfunction and low-level in vitro resistance to thrombin-induced platelet microbicidal protein. J Infect Dis 2004; 190:1140–1149 [View Article][PubMed]
     [Google Scholar]
  6. Kuehl R, Morata L, Meylan S, Mensa J, Soriano A. When antibiotics fail: a clinical and microbiological perspective on antibiotic tolerance and persistence of Staphylococcus aureus. J Antimicrob Chemother 2020; 75:1071–1086 [View Article][PubMed]
     [Google Scholar]
  7. Iung B, Duval X. Infective endocarditis: innovations in the management of an old disease. Nat Rev Cardiol 2019; 16:623–635 [View Article][PubMed]
     [Google Scholar]
  8. Urish KL, Cassat JE. Staphylococcus aureus Osteomyelitis: bone, bugs, and surgery. Infect Immun 2020; 88:e00932–19 [View Article][PubMed]
     [Google Scholar]
  9. Go CH, Clarke TA, Cunha BA. Persistent septic arthritis with recurrent bacteremia as a result of a tolerant strain of Staphylococcus aureus. Heart Lung 2000; 29:383–385 [View Article][PubMed]
     [Google Scholar]
  10. Safdar A, Rolston KVI. Vancomycin tolerance, a potential mechanism for refractory Gram-positive bacteremia observational study in patients with cancer. Cancer 2006; 106:1815–1820 [View Article][PubMed]
     [Google Scholar]
  11. Li L, Yeaman MR, Bayer AS, Xiong YQ. Phenotypic and genotypic characteristics of methicillin-resistant Staphylococcus aureus (MRSA) related to persistent endovascular infection. Antibiotics 2019; 8:71 [View Article][PubMed]
     [Google Scholar]
  12. Liu Q, Mazhar M, Miller LS. Immune and inflammatory reponses to Staphylococcus aureus skin infections. Curr Dermatol Rep 2018; 7:338–349 [View Article][PubMed]
     [Google Scholar]
  13. Ehrnström B, Kojen JF, Giambelluca M, Ryan L, Moen SH et al. Tlr8 and complement C5 induce cytokine release and thrombin activation in human whole blood challenged with gram-positive bacteria. J Leukoc Biol 2020; 107:673–683 [View Article][PubMed]
     [Google Scholar]
  14. Ellson CD, Davidson K, Ferguson GJ, O'Connor R, Stephens LR et al. Neutrophils from p40phox-/- mice exhibit severe defects in NADPH oxidase regulation and oxidant-dependent bacterial killing. J Exp Med 2006; 203:1927–1937 [View Article][PubMed]
     [Google Scholar]
  15. Buvelot H, Posfay-Barbe KM, Linder P, Schrenzel J, Krause KH. Staphylococcus aureus, phagocyte NADPH oxidase and chronic granulomatous disease. FEMS Microbiol Rev 2017; 41:139–157 [View Article][PubMed]
     [Google Scholar]
  16. Painter KL, Hall A, Ha KP, Edwards AM. The Electron Transport Chain Sensitizes Staphylococcus aureus and Enterococcus faecalis to the Oxidative Burst. Infect Immun 2017; 85:e00659–17 [View Article][PubMed]
     [Google Scholar]
  17. Liu GY, Essex A, Buchanan JT, Datta V, Hoffman HM et al. Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J Exp Med 2005; 202:209–215 [View Article][PubMed]
     [Google Scholar]
  18. Cheng AG, DeDent AC, Schneewind O, Missiakas D. A play in four acts: Staphylococcus aureus abscess formation. Trends Microbiol 2011; 19:225–232 [View Article][PubMed]
     [Google Scholar]
  19. Spaan AN, van Strijp JAG, Torres VJ. Leukocidins: staphylococcal Bi-component pore-forming toxins find their receptors. Nat Rev Microbiol 2017; 15:435–447 [View Article][PubMed]
     [Google Scholar]
  20. Priest NK, Rudkin JK, Feil EJ, van den Elsen JM, Cheung A et al. From genotype to phenotype: can systems biology be used to predict Staphylococcus aureus virulence?. Nat Rev Microbiol 2012; 10:791–797 [View Article][PubMed]
     [Google Scholar]
  21. Villanueva M, García B, Valle J, Rapún B, Ruiz de Los Mozos I et al. Sensory deprivation in Staphylococcus aureus. Nat Commun 2018; 9:523 [View Article][PubMed]
     [Google Scholar]
  22. Painter KL, Strange E, Parkhill J, Bamford KB, Armstrong-James D et al. Staphylococcus aureus adapts to oxidative stress by producing H2O2-resistant small-colony variants via the SOS response. Infect Immun 2015; 83:1830–1844 [View Article][PubMed]
     [Google Scholar]
  23. Mlynek KD, Sause WE, Moormeier DE, Sadykov MR, Hill KR et al. Nutritional regulation of the sae two-component system by CodY in Staphylococcus aureus. J Bacteriol 2018; 200:e00012–00018 [View Article][PubMed]
     [Google Scholar]
  24. van Schaik W, Abee T. The role of sigmaB in the stress response of Gram-positive bacteria - targets for food preservation and safety. Curr Opin Biotechnol 2005; 16:218–224 [View Article][PubMed]
     [Google Scholar]
  25. Chan PF, Foster SJ, Ingham E, Clements MO. The Staphylococcus aureus alternative sigma factor sigmaB controls the environmental stress response but not starvation survival or pathogenicity in a mouse abscess model. J Bacteriol 1998; 180:6082–6089 [View Article][PubMed]
     [Google Scholar]
  26. Pané-Farré J, Jonas B, Förstner K, Engelmann S, Hecker M. The sigmaB regulon in Staphylococcus aureus and its regulation. Int J Med Microbiol 2006; 296:237–258 [View Article][PubMed]
     [Google Scholar]
  27. Cebrián G, Sagarzazu N, Aertsen A, Pagán R, Condón S et al. Role of the alternative sigma factor sigma on Staphylococcus aureus resistance to stresses of relevance to food preservation. J Appl Microbiol 2009; 107:187–196 [View Article][PubMed]
     [Google Scholar]
  28. Kenny JG, Ward D, Josefsson E, Jonsson IM, Hinds J et al. The Staphylococcus aureus response to unsaturated long chain free fatty acids: survival mechanisms and virulence implications. PLoS One 2009; 4:e4344 [View Article][PubMed]
     [Google Scholar]
  29. Bischoff M, Entenza JM, Giachino P. Influence of a functional sigB operon on the global regulators sar and agr in Staphylococcus aureus. J Bacteriol 2001; 183:5171–5179 [View Article][PubMed]
     [Google Scholar]
  30. Horsburgh MJ, Aish JL, White IJ, Shaw L, Lithgow JK et al. sigmaB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325-4. J Bacteriol 2002; 184:5457–5467 [View Article][PubMed]
     [Google Scholar]
  31. Li D, Renzoni A, Estoppey T, Bisognano C, Francois P et al. Induction of fibronectin adhesins in quinolone-resistant Staphylococcus aureus by subinhibitory levels of ciprofloxacin or by sigma B transcription factor activity is mediated by two separate pathways. Antimicrob Agents Chemother 2005; 49:916–924 [View Article][PubMed]
     [Google Scholar]
  32. Shaw LN, Aish J, Davenport JE, Brown MC, Lithgow JK et al. Investigations into sigmaB-modulated regulatory pathways governing extracellular virulence determinant production in Staphylococcus aureus. J Bacteriol 2006; 188:6070–6080 [View Article][PubMed]
     [Google Scholar]
  33. Jonsson IM, Arvidson S, Foster S, Tarkowski A. Sigma factor B and RsbU are required for virulence in Staphylococcus aureus-induced arthritis and sepsis. Infect Immun 2004; 72:6106–6111 [View Article][PubMed]
     [Google Scholar]
  34. Lauderdale KJ, Boles BR, Cheung AL, Horswill AR. Interconnections between Sigma B, agr, and proteolytic activity in Staphylococcus aureus biofilm maturation. Infect Immun 2009; 77:1623–1635 [View Article][PubMed]
     [Google Scholar]
  35. Tuchscherr L, Geraci J, Löffler B. Staphylococcus aureus regulator Sigma B is important to develop chronic infections in hematogenous murine osteomyelitis model. Pathogens 2017; 6:31 [View Article][PubMed]
     [Google Scholar]
  36. Tuchscherr L, Bischoff M, Lattar SM, Noto Llana M, Pförtner H et al. Sigma Factor SigB Is Crucial to Mediate Staphylococcus aureus Adaptation during Chronic Infections. PLoS Pathog 2015; 11:e1004870 [View Article][PubMed]
     [Google Scholar]
  37. Pförtner H, Burian MS, Michalik S, Depke M, Hildebrandt P et al. Activation of the alternative sigma factor SigB of Staphylococcus aureus following internalization by epithelial cells - an in vivo proteomics perspective. Int J Med Microbiol 2014; 304:177–187 [View Article][PubMed]
     [Google Scholar]
  38. Wu S, de Lencastre H, Tomasz A. Sigma-B, a putative operon encoding alternate sigma factor of Staphylococcus aureus RNA polymerase: molecular cloning and DNA sequencing. J Bacteriol 1996; 178:6036–6042 [View Article][PubMed]
     [Google Scholar]
  39. Bischoff M, Berger-Bächi B. Teicoplanin stress-selected mutations increasing sigma(B) activity in Staphylococcus aureus. Antimicrob Agents Chemother 2001; 45:1714–1720 [View Article][PubMed]
     [Google Scholar]
  40. Bischoff M, Roos M, Putnik J, Wada A, Glanzmann P et al. Involvement of multiple genetic loci in Staphylococcus aureus teicoplanin resistance. FEMS Microbiol Lett 2001; 194:77–82 [View Article][PubMed]
     [Google Scholar]
  41. Morikawa K, Maruyama A, Inose Y, Higashide M, Hayashi H et al. Overexpression of sigma factor, sigma(B), urges Staphylococcus aureus to thicken the cell wall and to resist beta-lactams. Biochem Biophys Res Commun 2001; 288:385–389 [View Article][PubMed]
     [Google Scholar]
  42. Price CT, Singh VK, Jayaswal RK, Wilkinson BJ, Gustafson JE. Pine oil cleaner-resistant Staphylococcus aureus: reduced susceptibility to vancomycin and oxacillin and involvement of SigB. Appl Environ Microbiol 2002; 68:5417–5421 [View Article][PubMed]
     [Google Scholar]
  43. Singh VK, Schmidt JL, Jayaswal RK, Wilkinson BJ. Impact of sigB mutation on Staphylococcus aureus oxacillin and vancomycin resistance varies with parental background and method of assessment. Int J Antimicrob Agents 2003; 21:256–261 [View Article][PubMed]
     [Google Scholar]
  44. Schulthess B, Meier S, Homerova D, Goerke C, Wolz C et al. Functional characterization of the sigmaB-dependent yabJ-spoVG operon in Staphylococcus aureus: role in methicillin and glycopeptide resistance. Antimicrob Agents Chemother 2009; 53:1832–1839 [View Article][PubMed]
     [Google Scholar]
  45. Balaban NQ, Helaine S, Lewis K, Ackermann M, Aldridge B et al. Definitions and guidelines for research on antibiotic persistence. Nat Rev Microbiol 2019; 17:441–448 [View Article][PubMed]
     [Google Scholar]
  46. Reiss S, Pané-Farré J, Fuchs S, François P, Liebeke M et al. Global analysis of the Staphylococcus aureus response to mupirocin. Antimicrob Agents Chemother 2012; 56:787–804 [View Article][PubMed]
     [Google Scholar]
  47. Hessling B, Bonn F, Otto A, Herbst FA, Rappen GM et al. Global proteome analysis of vancomycin stress in Staphylococcus aureus. Int J Med Microbiol 2013; 303:624–634 [View Article][PubMed]
     [Google Scholar]
  48. Kubistova L, Dvoracek L, Tkadlec J, Melter O, Licha I. Environmental Stress Affects the Formation of Staphylococcus aureus Persisters Tolerant to Antibiotics. Microb Drug Resist 2018; 24:547–555 [View Article][PubMed]
     [Google Scholar]
  49. Gründling A, Schneewind O. Genes required for glycolipid synthesis and lipoteichoic acid anchoring in Staphylococcus aureus. J Bacteriol 2007; 189:2521–2530 [View Article][PubMed]
     [Google Scholar]
  50. Donegan NP, Cheung AL. Regulation of the mazEF toxin-antitoxin module in Staphylococcus aureus and its impact on sigB expression. J Bacteriol 2009; 191:2795–2805 [View Article][PubMed]
     [Google Scholar]
  51. Wiegand I, Hilpert K, Hancock REW. Agar and broth dilution methods to determine the minimal inhibitory concentration (MIC) of antimicrobial substances. Nat Protoc 2008; 3:163–175 [View Article][PubMed]
     [Google Scholar]
  52. Pader V, Hakim S, Painter KL, Wigneshweraraj S, Clarke TB et al. Staphylococcus aureus inactivates daptomycin by releasing membrane phospholipids. Nat Microbiol 2016; 2:16194 [View Article][PubMed]
     [Google Scholar]
  53. Krishna A, Holden MTG, Peacock SJ, Edwards AM, Wigneshweraraj S. Naturally occurring polymorphisms in the virulence regulator Rsp modulate Staphylococcus aureus survival in blood and antibiotic susceptibility. Microbiology 2018; 164:1189–1195 [View Article][PubMed]
     [Google Scholar]
  54. Atwood DN, Beenken KE, Lantz TL, Meeker DG, Lynn WB et al. Regulatory mutations impacting antibiotic susceptibility in an established Staphylococcus aureus biofilm. Antimicrob Agents Chemother 2016; 60:1826–1829 [View Article][PubMed]
     [Google Scholar]
  55. Mishra NN, Liu GY, Yeaman MR, Nast CC, Proctor RA et al. Carotenoid-related alteration of cell membrane fluidity impacts Staphylococcus aureus susceptibility to host defense peptides. Antimicrob Agents Chemother 2011; 55:526–531 [View Article][PubMed]
     [Google Scholar]
  56. Malachowa N, Whitney AR, Kobayashi SD, Sturdevant DE, Kennedy AD et al. Global changes in Staphylococcus aureus gene expression in human blood. PLoS One 2011; 6:e18617 [View Article][PubMed]
     [Google Scholar]
  57. Guldimann C, Boor KJ, Wiedmann M, Guariglia-Oropeza V. Resilience in the face of uncertainty: sigma factor B fine-tunes gene expression to support homeostasis in Gram-positive bacteria. Appl Environ Microbiol 2016; 82:4456–4469 [View Article][PubMed]
     [Google Scholar]
  58. Pisu D, Provvedi R, Espinosa DM, Payan JB, Boldrin F et al. The alternative sigma factors sigE and SigB are involved in tolerance and persistence to antitubercular drugs. Antimicrob Agents Chemother 2017; 61:e01596–17 [View Article][PubMed]
     [Google Scholar]
  59. Knudsen GM, Ng Y, Gram L. Survival of bactericidal antibiotic treatment by a persister subpopulation of Listeria monocytogenes. Appl Environ Microbiol 2013; 79:7390–7397 [View Article][PubMed]
     [Google Scholar]
  60. Liu CI, Liu GY, Song Y, Yin F, Hensler ME et al. A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence. Science 2008; 319:1391–1394 [View Article][PubMed]
     [Google Scholar]
  61. Palmer ME, Chaturongakul S, Wiedmann M, Boor KJ. The Listeria monocytogenes σB regulon and its virulence-associated functions are inhibited by a small molecule. mBio 2011; 2:e00241–11 [View Article][PubMed]
     [Google Scholar]
  62. Clauditz A, Resch A, Wieland KP, Peschel A, Götz F. Staphyloxanthin plays a role in the fitness of Staphylococcus aureus and its ability to cope with oxidative stress. Infect Immun 2006; 74:4950–4953 [View Article][PubMed]
     [Google Scholar]
  63. Ringus DL, Gaballa A, Helmann JD, Wiedmann M, Boor KJ. Fluoro-phenyl-styrene-sulfonamide, a novel inhibitor of σB activity, prevents the activation of σB by environmental and energy stresses in Bacillus subtilis. J Bacteriol 2013; 195:2509–2517 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000983
Loading
The general stress response of Staphylococcus aureus promotes tolerance of antibiotics and survival in whole human blood
Microbiology 166, 1088 (2020); https://doi.org/10.1099/mic.0.000983
/content/journal/micro/10.1099/mic.0.000983
/content/journal/micro/10.1099/mic.0.000983
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error