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Prediction of Transcription Factors and Their Involvement in Regulating Rifamycin Production in Amycolatopsis mediterranei S699

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Abstract

Amycolatopsis mediterranei S699 produces rifamycin B and successors of this strain are in use for the industrial production of rifamycin B. Semisynthetic derivatives of rifamycin B are used against Mycobacterium tuberculosis that causes tuberculosis. Although the rifamycin biosynthetic gene cluster was characterized two decades ago, the regulation of rifamycin B biosynthesis in Amycolatopsis mediterranei S699 is poorly understood. In this study, we analysed the genome and proteome of Amycolatopsis mediterranei S699 and identified 1102 transcription factors which comprise about 10% of the total genome. Using interactomics approaches we delineated 30 unique transcription factors directly involved in secondary metabolism that regulate rifamycin B biosynthesis. We also predict the role of RifN as hub in controlling the regulation of other genes involved in rifamycin biosynthesis. RifN is important for maintaining the integrity of the rifamycin-network. Thus, these transcription factor can be exploited to improve rifamycin B production in Amycolatopsis mediterranei S699.

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References

  1. Romero-Rodríguez A, Robledo-Casados I, Sánchez S (2015) An overview on transcriptional regulators in Streptomyces. Biochim Biophys Acta 1849:1017–1039. https://doi.org/10.1016/j.bbagrm.2015.06.007

    Article  CAS  PubMed  Google Scholar 

  2. Seshasayee AS, Sivaraman K, Luscombe NM (2011) An overview of prokaryotic transcription factors: a summary of function and occurrence in bacterial genomes. Subcell Biochem 52:7–23. https://doi.org/10.1007/978-90-481-9069-0_2

    Article  CAS  PubMed  Google Scholar 

  3. Lal R, Kumari R, Kaur H, Khanna R, Dhingra N, Tuteja D (2000) Regulation and manipulation of the gene clusters encoding type –I PKSs. Trends Biotechnol 18:264–274. https://doi.org/10.1016/s0167-7799(00)01443-8

    Article  CAS  PubMed  Google Scholar 

  4. Aristoff PA, Garcia GA, Kirchhoff PD, Showalter HH (2010) Rifamycins–obstacles and opportunities. Tuberculosis 90:94–118. https://doi.org/10.1016/j.tube.2010.02.001

    Article  CAS  PubMed  Google Scholar 

  5. Kumari R, Singh P, Lal R (2016) Genetics and Genomics of the Genus Amycolatopsis. Indian J Microbiol 56:233–246. https://doi.org/10.1007/s12088-016-0590-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gatta L, Scarpignato C (2017) Systematic review with meta-analysis: rifaximin is effective and safe for the treatment of small intestine bacterial overgrowth. Aliment Pharmacol Ther 45:604–616. https://doi.org/10.1111/apt.13928

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kumar A, Chettiar S, Parish T (2017) Current challenges in drug discovery for tuberculosis. Expert Opin Drug Discov 12:1–4. https://doi.org/10.1080/17460441.2017.1255604

    Article  PubMed  Google Scholar 

  8. Schön T, Chryssanthou E (2017) Minimal inhibitory concentration distributions for Mycobacterium avium complex—towards evidence based susceptibility breakpoints. Int J Infect Dis 55:122–124. https://doi.org/10.1016/j.ijid.2016.12.027

    Article  CAS  PubMed  Google Scholar 

  9. Prasad R, Singh A, Balasubramanian V, Gupta N (2017) Extensively drug-resistant tuberculosis in India: current evidence on diagnosis & management. Indian J Med Res 145:271–293. https://doi.org/10.4103/ijmr.IJMR_177_16

    Article  PubMed  PubMed Central  Google Scholar 

  10. Matteelli A, Roggi A, Carvalho AC (2014) Extensively drug-resistant tuberculosis: epidemiology and management. Clin Epidemiol 6:111–118. https://doi.org/10.2147/CLEPS35839

    Article  PubMed  PubMed Central  Google Scholar 

  11. Haydel SE (2010) Extensively drug-resistant tuberculosis: a sign of the times and an impetus for antimicrobial discovery. Pharmaceuticals (Basel) 3:2268–2290. https://doi.org/10.3390/ph3072268

    Article  CAS  Google Scholar 

  12. Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Martín-Casabona N, Drobniewski F, Gilpin C, Havelková M, Lepe R, Lumb R, Metchock B, Portaels F, Rodrigues MF, Rüsch-Gerdes S, Van Deun A, Vincent V, Laserson K, Wells C, Cegielski JP (2007) Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 13:380–387. https://doi.org/10.3201/eid1303.061400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. August PR, Tang L, Yoon YJ, Ning S, Muller R, Yu TW, Taylor M, Hoffman D, Kim CG, Zhang X, Hutchinson CR, Floss HG (1998) Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699. Chem Biol 5:69–79. https://doi.org/10.1016/S1074-5521(98)90141-7

    Article  CAS  PubMed  Google Scholar 

  14. Xu J, Wan E, Kim CJ, Floss HG, Mahmud T (2005) Identification of tailoring genes involved in the modification of the polyketide backbone of rifamycin B by Amycolatopsis mediterranei S699. Microbiol 151:2515–2528. https://doi.org/10.1099/mic.0.28138-0

    Article  CAS  Google Scholar 

  15. Nigam A, Almabruk KH, Saxena A, Jongtae Y, Mukherjee U, Kaur H, Kohli P, Kumari R, Singh P, Zakharov LN, Singh Y, Mahmud T, Lal R (2014) Modification of rifamycin polyketide backbone in Amycolatopsis mediterranei leads to the production of a new rifamycin B analog with an improved drug activity against rifampicin-resistant Mycobacterium tuberculosis strains. J Biol Chem 289:21142–21152. https://doi.org/10.1074/jbc.M114.572636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Singh P, Kumari R, Lal R (2017) Bedaquiline: fallible hope against drug resistant tuberculosis. Indian J Microbiol 57:371–377. https://doi.org/10.1007/s12088-017-0674-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. McArthur M, Bibb MJ (2008) Manipulating and understanding antibiotic production in Streptomyces coelicolor A3(2) with decoy oligonucleotides. Proc Natl Acad Sci USA 105:1020–1025. https://doi.org/10.1073/pnas0710724105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang J, Xu J, Luo S, Ma Z, Bechthold A, Yu X (2018) AdpAsd, a positive regulator for morphological development and toyocamycin biosynthesis in Streptomyces diastatochromogenes 1628. Curr Microbiol 75:1345–1351. https://doi.org/10.1007/s00284-018-1529-6

    Article  CAS  PubMed  Google Scholar 

  19. Xu X, Wang J, Bechthold A, Ma Z, Yu X (2017) Selection of an efficient promoter and its application in toyocamycin production improvement in Streptomyces diastatochromogenes 1628. World J Microbiol Biotechnol 33:30–38. https://doi.org/10.1007/s11274-016-2194-1

    Article  CAS  PubMed  Google Scholar 

  20. Guo J, Frost JW (2002) Biosynthesis of 1-deoxy-1-imino-D-erythrose 4-phosphate: a defining metabolite in the aminoshikimate pathway. J Am Chem Soc 124:528–529. https://doi.org/10.1021/ja016963v

    Article  CAS  PubMed  Google Scholar 

  21. Verma M, Kaur J, Kumar M, Kumari K, Saxena A, Anand S, Nigam A, Ravi V, Raghuvanshi S, Khurana P, Tyagi AK, Khurana JP, Lal R (2011) Whole genome sequence of Rifamycin B- producing strain Amycolatopsis mediterranei S699. J Bacteriol 193:5562–5563. https://doi.org/10.1128/JB.05819-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. UniProt Consortium (2007) The universal protein resource (UniProt). Nucleic Acids Res 36:D190–195. https://doi.org/10.1093/nar/gkm895(Database issue)

    Article  CAS  Google Scholar 

  23. Mering CV, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B (2003) STRING: a database of predicted functional associations between proteins. Nucleic Acids Res 31:258–261. https://doi.org/10.1093/nar/gkg034

    Article  CAS  Google Scholar 

  24. Ortet P, De Luca G, Whitworth DE, Barakat M (2012) P2TF: a comprehensive resource for analysis of prokaryotic transcription factors. BMC Genomics 13:628–636. https://doi.org/10.1186/1471-2164-13-628

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T (2003) Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 13:2498–2504. https://doi.org/10.1101/gr.1239303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gupta V, Haider S, Sood U, Gilbert JA, Ramjee M, Forbes K, Singh Y, Lopes BS, Lal R (2016) Comparative genomic analysis of novel Acinetobacter symbionts: a combined systems biology and genomics approach. Sci Rep 6:29043–29055. https://doi.org/10.1038/srep29043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Grant JR, Stothard P (2008) The CGView server: a comparative genomics tool for circular genomes. Nucleic Acids Res 36:W181–W184. https://doi.org/10.1093/nar/gkn179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lei C, Wang J, Liu Y, Liu X, Zhao G, Wang J (2017) A feedback regulatory model for RifQ-mediated repression of rifamycin export in Amycolatopsis mediterranei. Microb Cell Fact 17:14–23. https://doi.org/10.1186/s12934-018-0863-5

    Article  CAS  Google Scholar 

  29. Li C, Liu X, Lei C, Yan H, Shao Z, Wang Y, Zhao G, Wang J, Ding X (2017) RifZ (AMED_0655) is a pathway-specific regulator for rifamycin biosynthesis in Amycolatopsis mediterranei. Appl Environ Microbiol 83:e03201–e3216. https://doi.org/10.1128/AEM.03201-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Świątek MA, Gubbens J, Bucca G, Song E, Yang YH, Laing E, Kim BG, Smith CP, van Wezel GP (2013) The ROK family regulator Rok7B7 pleiotropically affects xylose utilization, carbon catabolite repression, and antibiotic production in Streptomyces coelicolor. J Bacteriol 195:1236–1248. https://doi.org/10.1128/JB02191-12

    Article  PubMed  PubMed Central  Google Scholar 

  31. Grove A (2013) MarR family transcription factors. Curr Biol 23:R142–143. https://doi.org/10.1016/jcub201301013

    Article  CAS  PubMed  Google Scholar 

  32. Verma H, Dhingra GG, Sharma M, Gupta V, Negi RK, Singh Y, Lal R (2020) Comparative genomics of Sphingopyxis spp. unravelled functional attributes. Genomics 112:1956–1969. https://doi.org/10.1016/j.ygeno.2019.11.008

    Article  CAS  PubMed  Google Scholar 

  33. Sood U, Hira P, Kumar R, Bajaj A, Rao DLN, Lal R, Shakarad M (2019) Comparative genomic analyses reveal core-genome-wide genes under positive selection and major regulatory hubs in outlier strains of Pseudomonas aeruginosa. Front Microbiol 10:53–76. https://doi.org/10.3389/fmicb.2019.00053

    Article  PubMed  PubMed Central  Google Scholar 

  34. Kumar R, Verma H, Haider S, Bajaj A, Sood U, Ponnusamy K, Nagar S, Shakarad M, Negi RK, Singh Y, Khurana JP, Gilbert JA, Lal R (2017) Comparative genomic analysis reveals habitat-specific genes and regulatory hubs within the genus Novosphingobium. mSystems 2:e00020-17. https://doi.org/10.1128/mSystems.00020-17

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

RL acknowledges The National Academy of Sciences, India, for support under the NASI‐Senior Scientist Platinum Jubilee Fellowship Scheme. NS acknowledges Council of Scientific and Industrial Research, New Delhi (CSIR) for doctoral fellowship.

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Correspondence to Yogendra Singh or Rup Lal.

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Singhvi, N., Gupta, V., Singh, P. et al. Prediction of Transcription Factors and Their Involvement in Regulating Rifamycin Production in Amycolatopsis mediterranei S699. Indian J Microbiol 60, 310–317 (2020). https://doi.org/10.1007/s12088-020-00868-5

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