Current Genetics

, Volume 62, Issue 1, pp 59–65 | Cite as

Physiological roles of bacillithiol in intracellular metal processing

  • Zuelay Rosario-Cruz
  • Jeffrey M. BoydEmail author


Glutathione (GSH) is an abundantly produced low-molecular-weight (LMW) thiol in many organisms. However, a number of Gram-positive bacteria do not produce GSH, but instead produce bacillithiol (BSH) as one of the major LMW thiols. Similar to GSH, studies have found that BSH has various roles in the cell, including protection against hydrogen peroxide, hypochlorite and disulfide stress. BSH also participates in the detoxification of thiol-reactive antibiotics and the electrophilic metabolite methylglyoxal. Recently, a number of studies have highlighted additional roles for BSH in the processing of intracellular metals. Herein, we examine the potential functions of BSH in the biogenesis of Fe–S clusters, cytosolic metal buffering and the prevention of metal intoxication.


Low-molecular-weight thiols Bacillithiol Iron-sulfur cluster Iron Zinc Manganese Copper 










The authors would like to thank Rutgers University and the United States Department of Agriculture (MRF project NE–1028) for funding.


  1. Albrecht AG, Netz DJA, Miethke M et al (2010) SufU is an essential iron-sulfur cluster scaffold protein in Bacillus subtilis. J Bacteriol 192:1643–1651. doi: 10.1128/JB.01536-09 PubMedCentralCrossRefPubMedGoogle Scholar
  2. Bae T, Banger AK, Wallace A et al (2004) Staphylococcus aureus virulence genes identified by bursa aurealis mutagenesis and nematode killing. Proc Natl Acad Sci U S A 101:12312–12317. doi: 10.1073/pnas.0404728101 PubMedCentralCrossRefPubMedGoogle Scholar
  3. Chandrangsu P, Dusi R, Hamilton CJ, Helmann JD (2014) Methylglyoxal resistance in Bacillus subtilis: contributions of bacillithiol-dependent and independent pathways. Mol Microbiol 91:706–715. doi: 10.1111/mmi.12489 PubMedCentralCrossRefPubMedGoogle Scholar
  4. Chaudhuri RR, Allen AG, Owen PJ et al (2009) Comprehensive identification of essential Staphylococcus aureus genes using transposon-mediated differential hybridisation (TMDH). BMC Genom 10:291. doi: 10.1186/1471-2164-10-291 CrossRefGoogle Scholar
  5. Chi BK, Roberts AA, Huyen TTT et al (2013) S-bacillithiolation protects conserved and essential proteins against hypochlorite stress in Firmicutes bacteria. Antioxid Redox Signal 18:1273–1295. doi: 10.1089/ars.2012.4686 PubMedCentralCrossRefPubMedGoogle Scholar
  6. Ding H, Clark RJ (2004) Characterization of iron binding in IscA, an ancient iron-sulphur cluster assembly protein. Biochem J 379:433–440. doi: 10.1042/BJ20031702 PubMedCentralCrossRefPubMedGoogle Scholar
  7. Ding H, Clark RJ, Ding B (2004) IscA mediates iron delivery for assembly of iron-sulfur clusters in IscU under the limited accessible free iron conditions. J Biol Chem 279:37499–37504. doi: 10.1074/jbc.M404533200 CrossRefPubMedGoogle Scholar
  8. Fahey RC (2013) Glutathione analogs in prokaryotes. Biochim Biophys Acta 1830:3182–3198. doi: 10.1016/j.bbagen.2012.10.006 CrossRefPubMedGoogle Scholar
  9. Fahey RC, Brown WC, Adams WB, Worsham MB (1978) Occurrence of glutathione in bacteria. J Bacteriol 133:1126–1129PubMedCentralPubMedGoogle Scholar
  10. Fang Z, Dos Santos PC (2015) Protective role of bacillithiol in superoxide stress and Fe–S metabolism in Bacillus subtilis. Microbiologyopen. doi: 10.1002/mbo3.267 Google Scholar
  11. Feng Y, Zhong N, Rouhier N et al (2006) Structural insight into poplar glutaredoxin C1 with a bridging iron-sulfur cluster at the active site. Biochemistry 45:7998–8008. doi: 10.1021/bi060444t CrossRefPubMedGoogle Scholar
  12. Fey PD, Endres JL, Yajjala VK et al (2013) A genetic resource for rapid and comprehensive phenotype screening of nonessential Staphylococcus aureus genes. mBio 4:e00537-12. doi: 10.1128/mBio.00537-12 PubMedCentralCrossRefPubMedGoogle Scholar
  13. Gaballa A, Newton GL, Antelmann H et al (2010) Biosynthesis and functions of bacillithiol, a major low-molecular-weight thiol in Bacilli. Proc Natl Acad Sci U S A 107:6482–6486. doi: 10.1073/pnas.1000928107 PubMedCentralCrossRefPubMedGoogle Scholar
  14. Gaballa A, Chi BK, Roberts AA et al (2013) Redox regulation in Bacillus subtilis: the bacilliredoxins BrxA (YphP) and BrxB (YqiW) function in de-bacillithiolation of S-bacillithiolated OhrR and MetE. Antioxid Redox Signal 21:357–367. doi: 10.1089/ars.2013.5327 CrossRefGoogle Scholar
  15. Gunther MR, Hanna PM, Mason RP, Cohen MS (1995) Hydroxyl radical formation from cuprous ion and hydrogen peroxide: a spin-trapping study. Arch Biochem Biophys 316:515–522. doi: 10.1006/abbi.1995.1068 CrossRefPubMedGoogle Scholar
  16. Gutiérrez-Escobedo G, Orta-Zavalza E, Castaño I, De Las Peñas A (2013) Role of glutathione in the oxidative stress response in the fungal pathogen Candida glabrata. Curr Genet 59:91–106. doi: 10.1007/s00294-013-0390-1 CrossRefPubMedGoogle Scholar
  17. Handtke S, Schroeter R, Jürgen B et al (2014) Bacillus pumilus reveals a remarkably high resistance to hydrogen peroxide provoked oxidative stress. PLoS One 9:e85625. doi: 10.1371/journal.pone.0085625 PubMedCentralCrossRefPubMedGoogle Scholar
  18. Helbig K, Bleuel C, Krauss GJ, Nies DH (2008a) Glutathione and transition-metal homeostasis in Escherichia coli. J Bacteriol 190:5431–5438. doi: 10.1128/JB.00271-08 PubMedCentralCrossRefPubMedGoogle Scholar
  19. Helbig K, Grosse C, Nies DH (2008b) Cadmium toxicity in glutathione mutants of Escherichia coli. J Bacteriol 190:5439–5454. doi: 10.1128/JB.00272-08 PubMedCentralCrossRefPubMedGoogle Scholar
  20. Hood MI, Skaar EP (2012) Nutritional immunity: transition metals at the pathogen-host interface. Nat Rev Microbiol 10:525–537. doi: 10.1038/nrmicro2836 CrossRefPubMedGoogle Scholar
  21. Inaoka T, Matsumura Y, Tsuchido T (1999) SodA and manganese are essential for resistance to oxidative stress in growing and sporulating cells of Bacillus subtilis. J Bacteriol 181:1939–1943PubMedCentralPubMedGoogle Scholar
  22. Jang S, Imlay JA (2007) Micromolar intracellular hydrogen peroxide disrupts metabolism by damaging iron-sulfur enzymes. J Biol Chem 282:929–937. doi: 10.1074/jbc.M607646200 CrossRefPubMedGoogle Scholar
  23. Johnson MDL, Kehl-Fie TE, Klein R et al (2015) Role of copper efflux in pneumococcal pathogenesis and resistance to macrophage-mediated immune clearance. Infect Immun 83:1684–1694. doi: 10.1128/IAI.03015-14 PubMedCentralCrossRefPubMedGoogle Scholar
  24. Landry AP, Cheng Z, Ding H (2013) Iron binding activity is essential for the function of IscA in iron-sulphur cluster biogenesis. Dalton Trans 42:3100–3106. doi: 10.1039/c2dt32000b PubMedCentralCrossRefPubMedGoogle Scholar
  25. Ma Z, Chandrangsu P, Helmann TC et al (2014) Bacillithiol is a major buffer of the labile zinc pool in Bacillus subtilis. Mol Microbiol 94:756–770. doi: 10.1111/mmi.12794 PubMedCentralCrossRefPubMedGoogle Scholar
  26. Macomber L, Imlay JA (2009) The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity. Proc Natl Acad Sci U S A 106:8344–8349. doi: 10.1073/pnas.0812808106 PubMedCentralCrossRefPubMedGoogle Scholar
  27. Macomber L, Rensing C, Imlay JA (2007) Intracellular copper does not catalyze the formation of oxidative DNA damage in Escherichia coli. J Bacteriol 189:1616–1626. doi: 10.1128/JB.01357-06 PubMedCentralCrossRefPubMedGoogle Scholar
  28. Mapolelo DT, Zhang B, Naik SG et al (2012) Spectroscopic and functional characterization of iron-sulfur cluster-bound forms of Azotobacter vinelandii (Nif)IscA. Biochemistry 51:8071–8084. doi: 10.1021/bi3006658 PubMedCentralCrossRefPubMedGoogle Scholar
  29. Mashruwala AA, Pang YY, Rosario-Cruz Z et al (2015) Nfu facilitates the maturation of iron-sulfur proteins and participates in virulence in Staphylococcus aureus. Mol Microbiol 95:383–409. doi: 10.1111/mmi.12860 CrossRefPubMedGoogle Scholar
  30. Masip L, Veeravalli K, Georgiou G (2006) The many faces of glutathione in bacteria. Antioxid Redox Signal 8:753–762. doi: 10.1089/ars.2006.8.753 CrossRefPubMedGoogle Scholar
  31. Newton GL, Buchmeier N, Fahey RC (2008) Biosynthesis and functions of mycothiol, the unique protective thiol of Actinobacteria. Microbiol Mol Biol Rev 72:471–494. doi: 10.1128/MMBR.00008-08 PubMedCentralCrossRefPubMedGoogle Scholar
  32. Newton GL, Rawat M, La Clair JJ et al (2009) Bacillithiol is an antioxidant thiol produced in Bacilli. Nat Chem Biol 5:625–627. doi: 10.1038/nchembio.189 PubMedCentralCrossRefPubMedGoogle Scholar
  33. Newton GL, Fahey RC, Rawat M (2012) Detoxification of toxins by bacillithiol in Staphylococcus aureus. Microbiology 158:1117–1126. doi: 10.1099/mic.0.055715-0 PubMedCentralCrossRefPubMedGoogle Scholar
  34. Posada AC, Kolar SL, Dusi RG et al (2014) The importance of bacillithiol in the oxidative stress response of Staphylococcus aureus. Infect Immun 82:316–332. doi: 10.1128/IAI.01074-13 PubMedCentralCrossRefPubMedGoogle Scholar
  35. Pöther D-C, Gierok P, Harms M et al (2013) Distribution and infection-related functions of bacillithiol in Staphylococcus aureus. Int J Med Microbiol 303:114–123. doi: 10.1016/j.ijmm.2013.01.003 CrossRefPubMedGoogle Scholar
  36. Potter AJ, Trappetti C, Paton JC (2012) Streptococcus pneumoniae uses glutathione to defend against oxidative stress and metal ion toxicity. J Bacteriol 194:6248–6254. doi: 10.1128/JB.01393-12 PubMedCentralCrossRefPubMedGoogle Scholar
  37. Qi W, Li J, Chain CY et al (2012) Glutathione complexed Fe–S centers. J Am Chem Soc 134:10745–10748. doi: 10.1021/ja302186j PubMedCentralCrossRefPubMedGoogle Scholar
  38. Rajkarnikar A, Strankman A, Duran S et al (2013) Analysis of mutants disrupted in bacillithiol metabolism in Staphylococcus aureus. Biochem Biophys 436:128–133. doi: 10.1016/j.bbrc.2013.04.027 CrossRefGoogle Scholar
  39. Roberts AA, Sharma SV, Strankman A et al (2013) Mechanistic studies of FosB: a divalent-metal-dependent bacillithiol-S-transferase that mediates fosfomycin resistance in Staphylococcus aureus. Biochem J 451:69–79PubMedCentralCrossRefPubMedGoogle Scholar
  40. Rosario-Cruz Z, Chahal HK, Mike LA et al (2015) Bacillithiol has a role in Fe–S cluster biogenesis in Staphylococcus aureus. Mol Microbiol. doi: 10.1111/mmi.13115 Google Scholar
  41. Sharma SV, Arbach M, Roberts AA et al (2013) Biophysical features of bacillithiol, the glutathione surrogate of Bacillus subtilis and other Firmicutes. ChemBioChem 14:2160–2168. doi: 10.1002/cbic.201300404 PubMedCentralCrossRefPubMedGoogle Scholar
  42. Sobota JM, Imlay JA (2011) Iron enzyme ribulose-5-phosphate 3-epimerase in Escherichia coli is rapidly damaged by hydrogen peroxide but can be protected by manganese. Proc Natl Acad Sci U S A 108:5402–5407. doi: 10.1073/pnas.1100410108 PubMedCentralCrossRefPubMedGoogle Scholar
  43. Tuchscherr L, Löffler B (2015) Staphylococcus aureus dynamically adapts global regulators and virulence factor expression in the course from acute to chronic infection. Curr Genet. doi: 10.1007/s00294-015-0503-0 PubMedGoogle Scholar
  44. Valentino MD, Foulston L, Sadaka A, et al. (2014) Genes contributing to Staphylococcus aureus fitness in abscess- and infection-related ecologies. mBio 5:e01729–14. doi:  10.1128/mBio.01729-14 PubMedCentralCrossRefPubMedGoogle Scholar
  45. Vinella D, Brochier-Armanet C, Loiseau L et al (2009) Iron-sulfur (Fe/S) protein biogenesis: phylogenomic and genetic studies of A-type carriers. PLoS Genet 5:e1000497. doi: 10.1371/journal.pgen.1000497 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Biochemistry and MicrobiologyRutgers UniversityNew BrunswickUSA

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