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. 1996 Jun;178(11):3221–3231. doi: 10.1128/jb.178.11.3221-3231.1996

Global negative regulation of Streptomyces coelicolor antibiotic synthesis mediated by an absA-encoded putative signal transduction system.

P Brian 1, P J Riggle 1, R A Santos 1, W C Champness 1
PMCID: PMC178074  PMID: 8655502

Abstract

Streptomycete antibiotic synthesis is coupled to morphological differentiation such that antibiotics are produced as a colony sporulates. Streptomyces coelicolor produces several structurally and genetically distinct antibiotics. The S. coelicolor absA locus was defined by four UV-induced mutations that globally blocked antibiotic biosynthesis without blocking morphological differentiation. We show that the absA locus encodes a putative eubacterial two-component sensor kinase-response regulator system. All four mutations lie within a single open reading frame, designated absA1, which is predicted to encode a sensor histidine kinase. A second gene downstream of absA1, absA2, is predicted to encode the cognate response regulator. In marked contrast to the antibiotic-deficient phenotype of the previously described absA mutants, the phenotype caused by disruption mutations in the absA locus is precocious hyperproduction of the antibiotics actinorhodin and undecylprodigiosin. Precocious hyperproduction of these antibiotics is correlated with premature expression of XylE activity in a transcriptional fusion to an actinorhodin biosynthetic gene. We propose that the absA locus encodes a signal transduction mechanism that negatively regulates synthesis of the multiple antibiotics produced by S. coelicolor.

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Selected References

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  1. Adamidis T., Champness W. Genetic analysis of absB, a Streptomyces coelicolor locus involved in global antibiotic regulation. J Bacteriol. 1992 Jul;174(14):4622–4628. doi: 10.1128/jb.174.14.4622-4628.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Adamidis T., Riggle P., Champness W. Mutations in a new Streptomyces coelicolor locus which globally block antibiotic biosynthesis but not sporulation. J Bacteriol. 1990 Jun;172(6):2962–2969. doi: 10.1128/jb.172.6.2962-2969.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Babcock M. J., Kendrick K. E. Cloning of DNA involved in sporulation of Streptomyces griseus. J Bacteriol. 1988 Jun;170(6):2802–2808. doi: 10.1128/jb.170.6.2802-2808.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bainton N. J., Bycroft B. W., Chhabra S. R., Stead P., Gledhill L., Hill P. J., Rees C. E., Winson M. K., Salmond G. P., Stewart G. S. A general role for the lux autoinducer in bacterial cell signalling: control of antibiotic biosynthesis in Erwinia. Gene. 1992 Jul 1;116(1):87–91. doi: 10.1016/0378-1119(92)90633-z. [DOI] [PubMed] [Google Scholar]
  5. Bainton N. J., Stead P., Chhabra S. R., Bycroft B. W., Salmond G. P., Stewart G. S., Williams P. N-(3-oxohexanoyl)-L-homoserine lactone regulates carbapenem antibiotic production in Erwinia carotovora. Biochem J. 1992 Dec 15;288(Pt 3):997–1004. doi: 10.1042/bj2880997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Birch A., Häusler A., Hütter R. Genome rearrangement and genetic instability in Streptomyces spp. J Bacteriol. 1990 Aug;172(8):4138–4142. doi: 10.1128/jb.172.8.4138-4142.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bruton C. J., Guthrie E. P., Chater K. F. Phage vectors that allow monitoring of transcription of secondary metabolism genes in Streptomyces. Biotechnology (N Y) 1991 Jul;9(7):652–656. doi: 10.1038/nbt0791-652. [DOI] [PubMed] [Google Scholar]
  8. Champness W. C. New loci required for Streptomyces coelicolor morphological and physiological differentiation. J Bacteriol. 1988 Mar;170(3):1168–1174. doi: 10.1128/jb.170.3.1168-1174.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Champness W., Riggle P., Adamidis T., Vandervere P. Identification of Streptomyces coelicolor genes involved in regulation of antibiotic synthesis. Gene. 1992 Jun 15;115(1-2):55–60. doi: 10.1016/0378-1119(92)90540-6. [DOI] [PubMed] [Google Scholar]
  10. Chater K. F., Bruton C. J., King A. A., Suarez J. E. The expression of Streptomyces and Escherichia coli drug-resistance determinants cloned into the Streptomyces phage phi C31. Gene. 1982 Jul-Aug;19(1):21–32. doi: 10.1016/0378-1119(82)90185-8. [DOI] [PubMed] [Google Scholar]
  11. Chater K. F., Bruton C. J. Mutational cloning in Streptomyces and the isolation of antibiotic production genes. Gene. 1983 Dec;26(1):67–78. doi: 10.1016/0378-1119(83)90037-9. [DOI] [PubMed] [Google Scholar]
  12. Chater K. F. The improving prospects for yield increase by genetic engineering in antibiotic-producing Streptomycetes. Biotechnology (N Y) 1990 Feb;8(2):115–121. doi: 10.1038/nbt0290-115. [DOI] [PubMed] [Google Scholar]
  13. Chiang R. C., Cavicchioli R., Gunsalus R. P. Identification and characterization of narQ, a second nitrate sensor for nitrate-dependent gene regulation in Escherichia coli. Mol Microbiol. 1992 Jul;6(14):1913–1923. doi: 10.1111/j.1365-2958.1992.tb01364.x. [DOI] [PubMed] [Google Scholar]
  14. Corbell N., Loper J. E. A global regulator of secondary metabolite production in Pseudomonas fluorescens Pf-5. J Bacteriol. 1995 Nov;177(21):6230–6236. doi: 10.1128/jb.177.21.6230-6236.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dahl M. K., Msadek T., Kunst F., Rapoport G. The phosphorylation state of the DegU response regulator acts as a molecular switch allowing either degradative enzyme synthesis or expression of genetic competence in Bacillus subtilis. J Biol Chem. 1992 Jul 15;267(20):14509–14514. [PubMed] [Google Scholar]
  16. Davis N. K., Chater K. F. Spore colour in Streptomyces coelicolor A3(2) involves the developmentally regulated synthesis of a compound biosynthetically related to polyketide antibiotics. Mol Microbiol. 1990 Oct;4(10):1679–1691. doi: 10.1111/j.1365-2958.1990.tb00545.x. [DOI] [PubMed] [Google Scholar]
  17. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Engebrecht J., Silverman M. Identification of genes and gene products necessary for bacterial bioluminescence. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4154–4158. doi: 10.1073/pnas.81.13.4154. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Feitelson J. S., Malpartida F., Hopwood D. A. Genetic and biochemical characterization of the red gene cluster of Streptomyces coelicolor A3(2). J Gen Microbiol. 1985 Sep;131(9):2431–2441. doi: 10.1099/00221287-131-9-2431. [DOI] [PubMed] [Google Scholar]
  20. Fernández-Moreno M. A., Caballero J. L., Hopwood D. A., Malpartida F. The act cluster contains regulatory and antibiotic export genes, direct targets for translational control by the bldA tRNA gene of Streptomyces. Cell. 1991 Aug 23;66(4):769–780. doi: 10.1016/0092-8674(91)90120-n. [DOI] [PubMed] [Google Scholar]
  21. Fernández-Moreno M. A., Martín-Triana A. J., Martínez E., Niemi J., Kieser H. M., Hopwood D. A., Malpartida F. abaA, a new pleiotropic regulatory locus for antibiotic production in Streptomyces coelicolor. J Bacteriol. 1992 May;174(9):2958–2967. doi: 10.1128/jb.174.9.2958-2967.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Gramajo H. C., Takano E., Bibb M. J. Stationary-phase production of the antibiotic actinorhodin in Streptomyces coelicolor A3(2) is transcriptionally regulated. Mol Microbiol. 1993 Mar;7(6):837–845. doi: 10.1111/j.1365-2958.1993.tb01174.x. [DOI] [PubMed] [Google Scholar]
  23. Guthrie E. P., Chater K. F. The level of a transcript required for production of a Streptomyces coelicolor antibiotic is conditionally dependent on a tRNA gene. J Bacteriol. 1990 Nov;172(11):6189–6193. doi: 10.1128/jb.172.11.6189-6193.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Henikoff S. Unidirectional digestion with exonuclease III creates targeted breakpoints for DNA sequencing. Gene. 1984 Jun;28(3):351–359. doi: 10.1016/0378-1119(84)90153-7. [DOI] [PubMed] [Google Scholar]
  25. Henner D. J., Yang M., Ferrari E. Localization of Bacillus subtilis sacU(Hy) mutations to two linked genes with similarities to the conserved procaryotic family of two-component signalling systems. J Bacteriol. 1988 Nov;170(11):5102–5109. doi: 10.1128/jb.170.11.5102-5109.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hopwood D. A., Wright H. M. CDA is a new chromosomally-determined antibiotic from Streptomyces coelicolor A3(2). J Gen Microbiol. 1983 Dec;129(12):3575–3579. doi: 10.1099/00221287-129-12-3575. [DOI] [PubMed] [Google Scholar]
  27. Horinouchi S., Beppu T. A-factor as a microbial hormone that controls cellular differentiation and secondary metabolism in Streptomyces griseus. Mol Microbiol. 1994 Jun;12(6):859–864. doi: 10.1111/j.1365-2958.1994.tb01073.x. [DOI] [PubMed] [Google Scholar]
  28. Horinouchi S., Hara O., Beppu T. Cloning of a pleiotropic gene that positively controls biosynthesis of A-factor, actinorhodin, and prodigiosin in Streptomyces coelicolor A3(2) and Streptomyces lividans. J Bacteriol. 1983 Sep;155(3):1238–1248. doi: 10.1128/jb.155.3.1238-1248.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ishizuka H., Horinouchi S., Kieser H. M., Hopwood D. A., Beppu T. A putative two-component regulatory system involved in secondary metabolism in Streptomyces spp. J Bacteriol. 1992 Dec;174(23):7585–7594. doi: 10.1128/jb.174.23.7585-7594.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Janssen G. R., Bibb M. J. Derivatives of pUC18 that have BglII sites flanking a modified multiple cloning site and that retain the ability to identify recombinant clones by visual screening of Escherichia coli colonies. Gene. 1993 Feb 14;124(1):133–134. doi: 10.1016/0378-1119(93)90774-w. [DOI] [PubMed] [Google Scholar]
  31. Kieser H. M., Kieser T., Hopwood D. A. A combined genetic and physical map of the Streptomyces coelicolor A3(2) chromosome. J Bacteriol. 1992 Sep;174(17):5496–5507. doi: 10.1128/jb.174.17.5496-5507.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Laity C., Chater K. F., Lewis C. G., Buttner M. J. Genetic analysis of the phi C31-specific phage growth limitation (Pgl) system of Streptomyces coelicolor A3(2). Mol Microbiol. 1993 Jan;7(2):329–336. doi: 10.1111/j.1365-2958.1993.tb01124.x. [DOI] [PubMed] [Google Scholar]
  33. Laville J., Voisard C., Keel C., Maurhofer M., Défago G., Haas D. Global control in Pseudomonas fluorescens mediating antibiotic synthesis and suppression of black root rot of tobacco. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1562–1566. doi: 10.1073/pnas.89.5.1562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Lydiate D. J., Malpartida F., Hopwood D. A. The Streptomyces plasmid SCP2*: its functional analysis and development into useful cloning vectors. Gene. 1985;35(3):223–235. doi: 10.1016/0378-1119(85)90001-0. [DOI] [PubMed] [Google Scholar]
  35. MacNeil D. J., Gewain K. M., Ruby C. L., Dezeny G., Gibbons P. H., MacNeil T. Analysis of Streptomyces avermitilis genes required for avermectin biosynthesis utilizing a novel integration vector. Gene. 1992 Feb 1;111(1):61–68. doi: 10.1016/0378-1119(92)90603-m. [DOI] [PubMed] [Google Scholar]
  36. Magnuson R., Solomon J., Grossman A. D. Biochemical and genetic characterization of a competence pheromone from B. subtilis. Cell. 1994 Apr 22;77(2):207–216. doi: 10.1016/0092-8674(94)90313-1. [DOI] [PubMed] [Google Scholar]
  37. Malpartida F., Hopwood D. A. Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. 1984 May 31-Jun 6Nature. 309(5967):462–464. doi: 10.1038/309462a0. [DOI] [PubMed] [Google Scholar]
  38. Malpartida F., Niemi J., Navarrete R., Hopwood D. A. Cloning and expression in a heterologous host of the complete set of genes for biosynthesis of the Streptomyces coelicolor antibiotic undecylprodigiosin. Gene. 1990 Sep 1;93(1):91–99. doi: 10.1016/0378-1119(90)90141-d. [DOI] [PubMed] [Google Scholar]
  39. Martín J. F. Biosynthesis of polyene macrolide antibiotics. Annu Rev Microbiol. 1977;31:13–38. doi: 10.1146/annurev.mi.31.100177.000305. [DOI] [PubMed] [Google Scholar]
  40. Matsumoto A., Hong S. K., Ishizuka H., Horinouchi S., Beppu T. Phosphorylation of the AfsR protein involved in secondary metabolism in Streptomyces species by a eukaryotic-type protein kinase. Gene. 1994 Aug 19;146(1):47–56. doi: 10.1016/0378-1119(94)90832-x. [DOI] [PubMed] [Google Scholar]
  41. McGowan S., Sebaihia M., Jones S., Yu B., Bainton N., Chan P. F., Bycroft B., Stewart G. S., Williams P., Salmond G. P. Carbapenem antibiotic production in Erwinia carotovora is regulated by CarR, a homologue of the LuxR transcriptional activator. Microbiology. 1995 Mar;141(Pt 3):541–550. doi: 10.1099/13500872-141-3-541. [DOI] [PubMed] [Google Scholar]
  42. Merrick M. J. A morphological and genetic mapping study of bald colony mutants of Streptomyces coelicolor. J Gen Microbiol. 1976 Oct;96(2):299–315. doi: 10.1099/00221287-96-2-299. [DOI] [PubMed] [Google Scholar]
  43. Narva K. E., Feitelson J. S. Nucleotide sequence and transcriptional analysis of the redD locus of Streptomyces coelicolor A3(2). J Bacteriol. 1990 Jan;172(1):326–333. doi: 10.1128/jb.172.1.326-333.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Nohno T., Noji S., Taniguchi S., Saito T. The narX and narL genes encoding the nitrate-sensing regulators of Escherichia coli are homologous to a family of prokaryotic two-component regulatory genes. Nucleic Acids Res. 1989 Apr 25;17(8):2947–2957. doi: 10.1093/nar/17.8.2947. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Otten S. L., Ferguson J., Hutchinson C. R. Regulation of daunorubicin production in Streptomyces peucetius by the dnrR2 locus. J Bacteriol. 1995 Mar;177(5):1216–1224. doi: 10.1128/jb.177.5.1216-1224.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Parkinson J. S., Kofoid E. C. Communication modules in bacterial signaling proteins. Annu Rev Genet. 1992;26:71–112. doi: 10.1146/annurev.ge.26.120192.000443. [DOI] [PubMed] [Google Scholar]
  47. Piret J. M., Chater K. F. Phage-mediated cloning of bldA, a region involved in Streptomyces coelicolor morphological development, and its analysis by genetic complementation. J Bacteriol. 1985 Sep;163(3):965–972. doi: 10.1128/jb.163.3.965-972.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rabin R. S., Stewart V. Dual response regulators (NarL and NarP) interact with dual sensors (NarX and NarQ) to control nitrate- and nitrite-regulated gene expression in Escherichia coli K-12. J Bacteriol. 1993 Jun;175(11):3259–3268. doi: 10.1128/jb.175.11.3259-3268.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Rinehart K. L., Jr, Stroshane R. M. Biosynthesis of aminocyclitol antibiotics. J Antibiot (Tokyo) 1976 Apr;29(4):319–353. doi: 10.7164/antibiotics.29.319. [DOI] [PubMed] [Google Scholar]
  50. Rodicio M. R., Bruton C. J., Chater K. F. New derivatives of the Streptomyces temperate phage phi C31 useful for the cloning and functional analysis of Streptomyces DNA. Gene. 1985;34(2-3):283–292. doi: 10.1016/0378-1119(85)90137-4. [DOI] [PubMed] [Google Scholar]
  51. Rudd B. A., Hopwood D. A. A pigmented mycelial antibiotic in Streptomyces coelicolor: control by a chromosomal gene cluster. J Gen Microbiol. 1980 Aug;119(2):333–340. doi: 10.1099/00221287-119-2-333. [DOI] [PubMed] [Google Scholar]
  52. Rudd B. A., Hopwood D. A. Genetics of actinorhodin biosynthesis by Streptomyces coelicolor A3(2). J Gen Microbiol. 1979 Sep;114(1):35–43. doi: 10.1099/00221287-114-1-35. [DOI] [PubMed] [Google Scholar]
  53. Schauer A. T., Nelson A. D., Daniel J. B. Tn4563 transposition in Streptomyces coelicolor and its application to isolation of new morphological mutants. J Bacteriol. 1991 Aug;173(16):5060–5067. doi: 10.1128/jb.173.16.5060-5067.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Stein D., Cohen S. N. A cloned regulatory gene of Streptomyces lividans can suppress the pigment deficiency phenotype of different developmental mutants. J Bacteriol. 1989 Apr;171(4):2258–2261. doi: 10.1128/jb.171.4.2258-2261.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Tan H., Chater K. F. Two developmentally controlled promoters of Streptomyces coelicolor A3(2) that resemble the major class of motility-related promoters in other bacteria. J Bacteriol. 1993 Feb;175(4):933–940. doi: 10.1128/jb.175.4.933-940.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Vögtli M., Chang P. C., Cohen S. N. afsR2: a previously undetected gene encoding a 63-amino-acid protein that stimulates antibiotic production in Streptomyces lividans. Mol Microbiol. 1994 Nov;14(4):643–653. doi: 10.1111/j.1365-2958.1994.tb01303.x. [DOI] [PubMed] [Google Scholar]
  57. Weinrauch Y., Penchev R., Dubnau E., Smith I., Dubnau D. A Bacillus subtilis regulatory gene product for genetic competence and sporulation resembles sensor protein members of the bacterial two-component signal-transduction systems. Genes Dev. 1990 May;4(5):860–872. doi: 10.1101/gad.4.5.860. [DOI] [PubMed] [Google Scholar]
  58. Weston L. A., Kadner R. J. Role of uhp genes in expression of the Escherichia coli sugar-phosphate transport system. J Bacteriol. 1988 Aug;170(8):3375–3383. doi: 10.1128/jb.170.8.3375-3383.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Willey J., Santamaria R., Guijarro J., Geistlich M., Losick R. Extracellular complementation of a developmental mutation implicates a small sporulation protein in aerial mycelium formation by S. coelicolor. Cell. 1991 May 17;65(4):641–650. doi: 10.1016/0092-8674(91)90096-h. [DOI] [PubMed] [Google Scholar]
  60. Wright L. F., Hopwood D. A. Identification of the antibiotic determined by the SCP1 plasmid of Streptomyces coelicolor A3(2). J Gen Microbiol. 1976 Jul;95(1):96–106. doi: 10.1099/00221287-95-1-96. [DOI] [PubMed] [Google Scholar]

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