1887

Abstract

Cerulenin is an antibiotic that inhibits fatty acid synthesis by covalent modification of the active thiol of the chain-elongation subtypes of -ketoacyl-acyl carrier protein synthase. It also inhibits other processes that utilize essential thiols. Cerulenin has been widely reported to block protein secretion at sub-MIC levels, an effect that has been postulated to represent interference with membrane function through interference with normal fatty acid synthesis. This study confirms the profound reduction in extracellular proteins caused by low concentrations of the antibiotic, and shows by Northern blot hybridization that this reduction is due to interference with transcription. By exchanging promoters between , a gene that is inhibited by cerulenin, and , a gene that is not, it was also shown that the antibiotic does not block secretion. Subinhibitory concentrations of cerulenin were also found to block transcriptional activation of at least two regulatory determinants, and , that function by signal transduction. Interference with the activation of these and other regulatory determinants probably accounts for much of the inhibitory effect on exoprotein production of sub-MIC concentrations of cerulenin.

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2005-09-01
2019-10-18
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References

  1. Altenbern, R. A. ( 1977; ). Extreme sensitivity of staphylococcal enterotoxin B and C production to inhibition by cerulenin. Antimicrob Agents Chemother 11, 906–908.[CrossRef]
    [Google Scholar]
  2. Bremell, T., Lange, S., Yacoub, A., Ryden, C. & Tarkowski, A. ( 1991; ). Experimental Staphylococcus aureus arthritis in mice. Infect Immun 59, 2615–2623.
    [Google Scholar]
  3. Byers, D. M. & Meighen, E. A. ( 1989; ). Inhibition of Vibrio harveyi bioluminescence by cerulenin: in vivo evidence for covalent modification of the reductase enzyme involved in aldehyde synthesis. J Bacteriol 171, 3866–3871.
    [Google Scholar]
  4. Charpentier, E., Anton, A. I., Barry, P., Alfonso, B., Fang, Y. & Novick, R. P. ( 2004; ). Novel cassette-based shuttle vector system for gram-positive bacteria. Appl Environ Microbiol 70, 6076–6085.[CrossRef]
    [Google Scholar]
  5. Fournier, B., Klier, A. & Rapoport, G. ( 2001; ). The two-component system ArlS-ArlR is a regulator of virulence gene expression in Staphylococcus aureus. Mol Microbiol 41, 247–261.[CrossRef]
    [Google Scholar]
  6. Giraudo, A. T., Cheung, A. L. & Nagel, R. ( 1997; ). The sae locus of Staphylococcus aureus controls exoprotein synthesis at the transcriptional level. Arch Microbiol 168, 53–58.[CrossRef]
    [Google Scholar]
  7. Goldberg, I., Walker, J. R. & Bloch, K. ( 1973; ). Inhibition of lipid synthesis in Escherichia coli cells by the antibiotic cerulenin. Antimicrob Agents Chemother 3, 549–554.[CrossRef]
    [Google Scholar]
  8. Greenspan, M. D. & Mackow, R. C. ( 1977; ). The effect of cerulenin on sterol biosynthesis in Saccharomyces cerevisiae. Lipids 12, 729–740.[CrossRef]
    [Google Scholar]
  9. Hiltunen, M. & Soderhall, K. ( 1992; ). Inhibition of polyketide synthesis in Alternaria alternata by the fatty acid synthesis inhibitor cerulenin. Appl Environ Microbiol 58, 1043–1045.
    [Google Scholar]
  10. Jacques, N. A. ( 1983; ). Membrane perturbation by cerulenin modulates glucosyltransferase secretion and acetate uptake by Streptococcus salivarius. J Gen Microbiol 129, 3293–3302.
    [Google Scholar]
  11. Ji, G., Beavis, R. & Novick, R. P. ( 1997; ). Bacterial interference caused by autoinducing peptide variants. Science 276, 2027–2030.[CrossRef]
    [Google Scholar]
  12. Jochen, A. L., Hays, J. & Mick, G. ( 1995; ). Inhibitory effects of cerulenin on protein palmitoylation and insulin internalization in rat adipocytes. Biochim Biophys Acta 1259, 65–72.[CrossRef]
    [Google Scholar]
  13. Kreiswirth, B. N., Lofdahl, S., Betley, M. J., O'Reilly, M., Schlievert, P. M., Bergdoll, M. S. & Novick, R. P. ( 1983; ). The toxic shock syndrome exotoxin structural gene is not detectably transmitted by a prophage. Nature 305, 709–712.[CrossRef]
    [Google Scholar]
  14. Laemmli, U. K. ( 1970; ). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680–685.[CrossRef]
    [Google Scholar]
  15. Lina, G., Jarraud, S., Ji, G., Greenland, T., Pedraza, A., Etienne, J., Novick, R. P. & Vandenesch, F. ( 1998; ). Transmembrane topology and histidine protein kinase activity of AgrC, the agr signal receptor in Staphylococcus aureus. Mol Microbiol 28, 655–662.[CrossRef]
    [Google Scholar]
  16. Mantsala, P. ( 1982; ). Inhibition of protein secretion by cerulenin in Bacillus subtilis. J Gen Microbiol 128, 2967–2972.
    [Google Scholar]
  17. Mantsala, P. & Lehtinen, H. ( 1982; ). Secretion of beta-lactamase by Escherichia coli in vivo and in vitro: effect of cerulenin. Antonie Van Leeuwenhoek 48, 353–364.[CrossRef]
    [Google Scholar]
  18. Martinez, J. P., Elorza, M. V., Gozalbo, D. & Sentandreu, R. ( 1982; ). Regulation of alpha-galactosidase synthesis in Saccharomyces cerevisiae and effect of cerulenin on the secretion of this enzyme. Biochim Biophys Acta 716, 158–168.[CrossRef]
    [Google Scholar]
  19. Novick, R. P. ( 1991; ). Genetic systems in staphylococci. Methods Enzymol 204, 587–636.
    [Google Scholar]
  20. Novick, R. P. & Jiang, D. ( 2003; ). The staphylococcal saeRS system coordinates environmental signals with agr quorum sensing. Microbiology 149, 2709–2717.[CrossRef]
    [Google Scholar]
  21. Novick, R. P., Ross, H. F., Projan, S. J., Kornblum, J., Kreiswirth, B. & Moghazeh, S. ( 1993; ). Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J 12, 3967–3975.
    [Google Scholar]
  22. Novick, R. P., Projan, S. J., Kornblum, J., Ross, H. F., Ji, G., Kreiswirth, B., Vandenesch, F. & Moghazeh, S. ( 1995; ). The agr P2 operon: an autocatalytic sensory transduction system in Staphylococcus aureus. Mol Gen Genet 248, 446–458.[CrossRef]
    [Google Scholar]
  23. Price, A. C., Choi, K. H., Heath, R. J., Li, Z., White, S. W. & Rock, C. O. ( 2001; ). Inhibition of beta-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J Biol Chem 276, 6551–6559.[CrossRef]
    [Google Scholar]
  24. Saleh, F. A. & Freer, J. H. ( 1984; ). Inhibition of secretion of staphylococcal alpha toxin by cerulenin. J Med Microbiol 18, 205–216.[CrossRef]
    [Google Scholar]
  25. Somerville, G. A., Chaussee, M. S., Morgan, C. I., Fitzgerald, J. R., Dorward, D. W., Reitzer, L. J. & Musser, J. M. ( 2002; ). Staphylococcus aureus aconitase inactivation unexpectedly inhibits post-exponential-phase growth and enhances stationary-phase survival. Infect Immun 70, 6373–6382.[CrossRef]
    [Google Scholar]
  26. Straub, S. G., Yajima, H., Komatsu, M., Aizawa, T. & Sharp, G. W. ( 2002; ). The effects of cerulenin, an inhibitor of protein acylation, on the two phases of glucose-stimulated insulin secretion. Diabetes 51, S91–S95.[CrossRef]
    [Google Scholar]
  27. Tegmark, K., Karlsson, A. & Arvidson, S. ( 2000; ). Identification and characterization of SarH1, a new global regulator of virulence gene expression in Staphylococcus aureus. Mol Microbiol 37, 398–409.[CrossRef]
    [Google Scholar]
  28. Tremaine, M. T., Brockman, D. K. & Betley, M. J. ( 1993; ). Staphylococcal enterotoxin A gene (sea) expression is not affected by the accessory gene regulator (agr). Infect Immun 61, 356–359.
    [Google Scholar]
  29. Val, D. L. & Cronan, J. E., Jr ( 1998; ). In vivo evidence that S-adenosylmethionine and fatty acid synthesis intermediates are the substrates for the LuxI family of autoinducer synthases. J Bacteriol 180, 2644–2651.
    [Google Scholar]
  30. Vojtov, N., Ross, H. F. & Novick, R. P. ( 2002; ). Global repression of exotoxin synthesis by staphylococcal superantigens. Proc Natl Acad Sci U S A 99, 10102–10107.[CrossRef]
    [Google Scholar]
  31. Weinrick, B., Dunman, P. M., McAleese, F., Murphy, E., Projan, S. J., Fang, Y. & Novick, R. P. ( 2004; ). Effect of mild acid on gene expression in Staphylococcus aureus. J Bacteriol 186, 8407–8423.[CrossRef]
    [Google Scholar]
  32. Wright, J. S., 3rd, Jin, R. & Novick, R. P. ( 2005; ). Transient interference with staphylococcal quorum sensing blocks abscess formation. Proc Natl Acad Sci U S A 102, 1691–1696.[CrossRef]
    [Google Scholar]
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