1887

Abstract

Persisters are dormant antibiotic-tolerant cells that usually compose a small fraction of bacterial populations. In this work, we focused on the role of trehalose in persister formation. We found that the Δ mutant, which is unable to synthesize trehalose, produced increased levels of persisters in the early stationary phase and under heat stress conditions. The lack of trehalose in the Δ mutant resulted in oxidative stress, manifested by increased membrane lipid peroxidation after heat shock. Stationary Δ cells additionally exhibited increased levels of oxidized proteins and apurinic/apyrimidinic sites in DNA as compared to WT cells. Oxidative stress caused by the lack of trehalose was accompanied by the overproduction of extracellular indole, a signal molecule that has been shown to stimulate persister formation. Our major conclusion is that intracellular trehalose protects cells against oxidative stress and limits indole synthesis, which in turn inhibits the formation of persisters.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000012
2015-04-01
2021-07-29
Loading full text...

Full text loading...

/deliver/fulltext/micro/161/4/786.html?itemId=/content/journal/micro/10.1099/mic.0.000012&mimeType=html&fmt=ahah

References

  1. Allison K. R., Brynildsen M. P., Collins J. J. (2011). Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473, 216220. [View Article][PubMed] [Google Scholar]
  2. Amato S. M., Orman M. A., Brynildsen M. P. (2013). Metabolic control of persister formation in Escherichia coli. Mol Cell 50, 475487. [View Article][PubMed] [Google Scholar]
  3. Ami D., Natalello A., Schultz T., Gatti-Lafranconi P., Lotti M., Doglia S. M., de Marco A. (2009). Effects of recombinant protein misfolding and aggregation on bacterial membranes. Biochim Biophys Acta 1794, 263269. [View Article][PubMed] [Google Scholar]
  4. Balaban N. Q. (2011). Persistence: mechanisms for triggering and enhancing phenotypic variability. Curr Opin Genet Dev 21, 768775. [View Article][PubMed] [Google Scholar]
  5. Balaban N. Q., Merrin J., Chait R., Kowalik L., Leibler S. (2004). Bacterial persistence as a phenotypic switch. Science 305, 16221625. [View Article][PubMed] [Google Scholar]
  6. Barraud N., Buson A., Jarolimek W., Rice S. A. (2013). Mannitol enhances antibiotic sensitivity of persister bacteria in Pseudomonas aeruginosa biofilms. PLoS ONE 8, e84220. [View Article][PubMed] [Google Scholar]
  7. Bednarska N. G., Schymkowitz J., Rousseau F., Van Eldere J. (2013). Protein aggregation in bacteria: the thin boundary between functionality and toxicity. Microbiology 159, 17951806. [View Article][PubMed] [Google Scholar]
  8. Béranger F., Crozet C., Goldsborough A., Lehmann S. (2008). Trehalose impairs aggregation of PrPSc molecules and protects prion-infected cells against oxidative damage. Biochem Biophys Res Commun 374, 4448. [View Article][PubMed] [Google Scholar]
  9. Cecarini V., Gee J., Fioretti E., Amici M., Angeletti M., Eleuteri A. M., Keller J. N. (2007). Protein oxidation and cellular homeostasis: emphasis on metabolism. Biochim Biophys Acta 1773, 93104. [View Article][PubMed] [Google Scholar]
  10. Chandra G., Chater K. F., Bornemann S. (2011). Unexpected and widespread connections between bacterial glycogen and trehalose metabolism. Microbiology 157, 15651572. [View Article][PubMed] [Google Scholar]
  11. Churchward G., Belin D., Nagamine Y. (1984). A pSC101-derived plasmid which shows no sequence homology to other commonly used cloning vectors. Gene 31, 165171.[PubMed][CrossRef] [Google Scholar]
  12. Conlon B. P., Nakayasu E. S., Fleck L. E., LaFleur M. D., Isabella V. M., Coleman K., Leonard S. N., Smith R. D., Adkins J. N., Lewis K. (2013). Activated ClpP kills persisters and eradicates a chronic biofilm infection. Nature 503, 365370. [View Article][PubMed] [Google Scholar]
  13. da Costa Morato Nery D., da Silva C. G., Mariani D., Fernandes P. N., Pereira M. D., Panek A. D., Eleutherio E. C. (2008). The role of trehalose and its transporter in protection against reactive oxygen species. Biochim Biophys Acta 1780, 14081411. [View Article][PubMed] [Google Scholar]
  14. Datsenko K. A., Wanner B. L. (2000). One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc Natl Acad Sci U S A 97, 66406645. [View Article][PubMed] [Google Scholar]
  15. Diamant S., Eliahu N., Rosenthal D., Goloubinoff P. (2001). Chemical chaperones regulate molecular chaperones in vitro and in cells under combined salt and heat stresses. J Biol Chem 276, 3958639591. [View Article][PubMed] [Google Scholar]
  16. Domka J., Lee J., Wood T. K. (2006). YliH (BssR) and YceP (BssS) regulate Escherichia coli K-12 biofilm formation by influencing cell signaling. Appl Environ Microbiol 72, 24492459. [View Article][PubMed] [Google Scholar]
  17. Dörr T., Vulić M., Lewis K. (2010). Ciprofloxacin causes persister formation by inducing the TisB toxin in Escherichia coli. PLoS Biol 8, e1000317. [View Article][PubMed] [Google Scholar]
  18. Elbein A. D., Pan Y. T., Pastuszak I., Carroll D. (2003). New insights on trehalose: a multifunctional molecule. Glycobiology 13, 17R27R. [View Article][PubMed] [Google Scholar]
  19. García De Castro A., Bredholt H., Strøm A. R., Tunnacliffe A. (2000). Anhydrobiotic engineering of Gram-negative bacteria. Appl Environ Microbiol 66, 41424144. [View Article][PubMed] [Google Scholar]
  20. Gerdes K., Maisonneuve E. (2012). Bacterial persistence and toxin-antitoxin loci. Annu Rev Microbiol 66, 103123. [View Article][PubMed] [Google Scholar]
  21. Germain E., Castro-Roa D., Zenkin N., Gerdes K. (2013). Molecular mechanism of bacterial persistence by HipA. Mol Cell 52, 248254. [View Article][PubMed] [Google Scholar]
  22. Giaever H. M., Styrvold O. B., Kaasen I., Strøm A. R. (1988). Biochemical and genetic characterization of osmoregulatory trehalose synthesis in Escherichia coli. J Bacteriol 170, 28412849.[PubMed] [Google Scholar]
  23. Hengge-Aronis R., Klein W., Lange R., Rimmele M., Boos W. (1991). Trehalose synthesis genes are controlled by the putative sigma factor encoded by rpoS and are involved in stationary-phase thermotolerance in Escherichia coli. J Bacteriol 173, 79187924.[PubMed] [Google Scholar]
  24. Herdeiro R. S., Pereira M. D., Panek A. D., Eleutherio E. C. (2006). Trehalose protects Saccharomyces cerevisiae from lipid peroxidation during oxidative stress. Biochim Biophys Acta 1760, 340346. [View Article][PubMed] [Google Scholar]
  25. Hirakawa H., Inazumi Y., Masaki T., Hirata T., Yamaguchi A. (2005). Indole induces the expression of multidrug exporter genes in Escherichia coli. Mol Microbiol 55, 11131126. [View Article][PubMed] [Google Scholar]
  26. Hong S. H., Wang X., O’Connor H. F., Benedik M. J., Wood T. K. (2012). Bacterial persistence increases as environmental fitness decreases. Microb Biotechnol 5, 509522. [View Article][PubMed] [Google Scholar]
  27. Jain N. K., Roy I. (2009). Effect of trehalose on protein structure. Protein Sci 18, 2436.[PubMed] [Google Scholar]
  28. Johnson P. J., Levin B. R. (2013). Pharmacodynamics, population dynamics, and the evolution of persistence in Staphylococcus aureus. PLoS Genet 9, e1003123. [View Article][PubMed] [Google Scholar]
  29. Kandror O., DeLeon A., Goldberg A. L. (2002). Trehalose synthesis is induced upon exposure of Escherichia coli to cold and is essential for viability at low temperatures. Proc Natl Acad Sci U S A 99, 97279732. [View Article][PubMed] [Google Scholar]
  30. Kim Y., Wood T. K. (2010). Toxins Hha and CspD and small RNA regulator Hfq are involved in persister cell formation through MqsR in Escherichia coli. Biochem Biophys Res Commun 391, 209213. [View Article][PubMed] [Google Scholar]
  31. Kim J. S., Heo P., Yang T. J., Lee K. S., Cho D. H., Kim B. T., Suh J. H., Lim H. J., Shin D. et al. (2011). Selective killing of bacterial persisters by a single chemical compound without affecting normal antibiotic-sensitive cells. Antimicrob Agents Chemother 55, 53805383. [View Article][PubMed] [Google Scholar]
  32. Korch S. B., Henderson T. A., Hill T. M. (2003). Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol Microbiol 50, 11991213. [View Article][PubMed] [Google Scholar]
  33. Kuczyńska-Wiśnik D., Matuszewska E., Laskowska E. (2010). Escherichia coli heat-shock proteins IbpA and IbpB affect biofilm formation by influencing the level of extracellular indole. Microbiology 156, 148157. [View Article][PubMed] [Google Scholar]
  34. Kurisu S., Miya T., Terato H., Masaoka A., Ohyama Y., Kubo K., Ide H. (2001). Quantitation of DNA damage by an aldehyde reactive probe (ARP). Nucleic Acids Symp. Ser. 1, 4546. [View Article][PubMed] [Google Scholar]
  35. Kwan B. W., Valenta J. A., Benedik M. J., Wood T. K. (2013). Arrested protein synthesis increases persister-like cell formation. Antimicrob Agents Chemother 57, 14681473. [View Article][PubMed] [Google Scholar]
  36. Lebeaux D., Chauhan A., Létoffé S., Fischer F., de Reuse H., Beloin C., Ghigo J. M. (2014). pH-mediated potentiation of aminoglycosides kills bacterial persisters and eradicates in vivo biofilms. J Infect Dis 210, 13571366. [View Article][PubMed] [Google Scholar]
  37. Lee J., Zhang X. S., Hegde M., Bentley W. E., Jayaraman A., Wood T. K. (2008). Indole cell signaling occurs primarily at low temperatures in Escherichia coli. ISME J 2, 10071023. [View Article][PubMed] [Google Scholar]
  38. Lee H. H., Molla M. N., Cantor C. R., Collins J. J. (2010). Bacterial charity work leads to population-wide resistance. Nature 467, 8285. [View Article][PubMed] [Google Scholar]
  39. Leszczy. ska D., Matuszewska E., Kuczynska-Wisnik D., Furmanek-Blaszk B., Laskowska E. ń(2013). The formation of persister cells in stationary-phase cultures of Escherichia coli is associated with the aggregation of endogenous proteins. PLoS ONE 8, e54737. [View Article][PubMed] [Google Scholar]
  40. Leung V., Lévesque C. M. (2012). A stress-inducible quorum-sensing peptide mediates the formation of persister cells with noninherited multidrug tolerance. J Bacteriol 194, 22652274. [View Article][PubMed] [Google Scholar]
  41. Levine R. L., Garland D., Oliver C. N., Amici A., Climent I., Lenz A. G., Ahn B. W., Shaltiel S., Stadtman E. R. (1990). Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol 186, 464478. [View Article][PubMed] [Google Scholar]
  42. Lewis K. (2010). Persister cells. Annu Rev Microbiol 64, 357372. [View Article][PubMed] [Google Scholar]
  43. Liu R., Barkhordarian H., Emadi S., Park C. B., Sierks M. R. (2005). Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42. Neurobiol Dis 20, 7481. [View Article][PubMed] [Google Scholar]
  44. Luo Y., Li W. M., Wang W. (2008). Trehalose: protector of antioxidant enzymes or reactive oxygen species scavenger under heat stress?Environ Exp Bot 63, 378384. [View Article] [Google Scholar]
  45. Maisonneuve E., Shakespeare L. J., Jørgensen M. G., Gerdes K. (2011). Bacterial persistence by RNA endonucleases. Proc Natl Acad Sci U S A 108, 1320613211. [View Article][PubMed] [Google Scholar]
  46. Montero M., Eydallin G., Viale A. M., Almagro G., Muñoz F. J., Rahimpour M., Sesma M. T., Baroja-Fernández E., Pozueta-Romero J. (2009). Escherichia coli glycogen metabolism is controlled by the PhoP-PhoQ regulatory system at submillimolar environmental Mg2+ concentrations, and is highly interconnected with a wide variety of cellular processes. Biochem J 424, 129141. [View Article][PubMed] [Google Scholar]
  47. Nguyen D., Joshi-Datar A., Lepine F., Bauerle E., Olakanmi O., Beer K., McKay G., Siehnel R., Schafhauser J. et al. (2011). Active starvation responses mediate antibiotic tolerance in biofilms and nutrient-limited bacteria. Science 334, 982986. [View Article][PubMed] [Google Scholar]
  48. Nocker A., Fernández P. S., Montijn R., Schuren F. (2012). Effect of air drying on bacterial viability: a multiparameter viability assessment. J Microbiol Methods 90, 8695. [View Article][PubMed] [Google Scholar]
  49. Oku K., Watanabe H., Kubota M., Fukuda S., Kurimoto M., Tsujisaka Y., Komori M., Inoue Y., Sakurai M. (2003). NMR and quantum chemical study on the OH...π and CH...O interactions between trehalose and unsaturated fatty acids: implication for the mechanism of antioxidant function of trehalose. J Am Chem Soc 125, 1273912748. [View Article][PubMed] [Google Scholar]
  50. Pan Y. T., Carroll J. D., Asano N., Pastuszak I., Edavana V. K., Elbein A. D. (2008). Trehalose synthase converts glycogen to trehalose. FEBS J 275, 34083420. [View Article][PubMed] [Google Scholar]
  51. Pomposiello P. J., Bennik M. H., Demple B. (2001). Genome-wide transcriptional profiling of the Escherichia coli responses to superoxide stress and sodium salicylate. J Bacteriol 183, 38903902. [View Article][PubMed] [Google Scholar]
  52. Poole K. (2012). Bacterial stress responses as determinants of antimicrobial resistance. J Antimicrob Chemother 67, 20692089. [View Article][PubMed] [Google Scholar]
  53. Purvis J. E., Yomano L. P., Ingram L. O. (2005). Enhanced trehalose production improves growth of Escherichia coli under osmotic stress. Appl Environ Microbiol 71, 37613769. [View Article][PubMed] [Google Scholar]
  54. Ruhal R., Kataria R., Choudhury B. (2013). Trends in bacterial trehalose metabolism and significant nodes of metabolic pathway in the direction of trehalose accumulation. Microb Biotechnol 6, 493502. [View Article][PubMed] [Google Scholar]
  55. Sambrook J., Fritsh E. F., Maniatis F. (1989).Molecular Cloning: a Laboratory Manual, 2nd edn. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory. [Google Scholar]
  56. Schultz T., Liu J., Capasso P., de Marco A. (2007). The solubility of recombinant proteins expressed in Escherichia coli is increased by otsA and otsB co-transformation. Biochem Biophys Res Commun 355, 234239. [View Article][PubMed] [Google Scholar]
  57. Singer M. A., Lindquist S. (1998). Multiple effects of trehalose on protein folding in vitro and in vivo. Mol Cell 1, 639648. [View Article][PubMed] [Google Scholar]
  58. Tanaka M., Machida Y., Niu S., Ikeda T., Jana N. R., Doi H., Kurosawa M., Nekooki M., Nukina N. (2004). Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med 10, 148154. [View Article][PubMed] [Google Scholar]
  59. Vega N. M., Allison K. R., Khalil A. S., Collins J. J. (2012). Signaling-mediated bacterial persister formation. Nat Chem Biol 8, 431433. [View Article][PubMed] [Google Scholar]
  60. Vega N. M., Allison K. R., Samuels A. N., Klempner M. S., Collins J. J. (2013). Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance. Proc Natl Acad Sci U S A 110, 1442014425. [View Article][PubMed] [Google Scholar]
  61. Wood T. K., Knabel S. J., Kwan B. W. (2013). Bacterial persister cell formation and dormancy. Appl Environ Microbiol 79, 71167121. [View Article][PubMed] [Google Scholar]
  62. Wu Y., Vulić M., Keren I., Lewis K. (2012). Role of oxidative stress in persister tolerance. Antimicrob Agents Chemother 56, 49224926. [View Article][PubMed] [Google Scholar]
  63. Yu W. B., Jiang T., Lan D. M., Lu J. H., Yue Z. Y., Wang J., Zhou P. (2012). Trehalose inhibits fibrillation of A53T mutant alpha-synuclein and disaggregates existing fibrils. Arch Biochem Biophys 523, 144150. [View Article][PubMed] [Google Scholar]
  64. Zhang Q., Yan T. (2012). Correlation of intracellular trehalose concentration with desiccation resistance of soil Escherichia coli populations. Appl Environ Microbiol 78, 74077413. [View Article][PubMed] [Google Scholar]
  65. Zhang J., Reddy J., Buckland B., Greasham R. (2003). Toward consistent and productive complex media for industrial fermentations: studies on yeast extract for a recombinant yeast fermentation process. Biotechnol Bioeng 82, 640652. [View Article][PubMed] [Google Scholar]
  66. Zheng M., Wang X., Templeton L. J., Smulski D. R., LaRossa R. A., Storz G. (2001). DNA microarray-mediated transcriptional profiling of the Escherichia coli response to hydrogen peroxide. J Bacteriol 183, 45624570. [View Article][PubMed] [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000012
Loading
/content/journal/micro/10.1099/mic.0.000012
Loading

Data & Media loading...

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