Genetic insights into the mechanism of teicoplanin self-resistance in Actinoplanes teichomyceticus


Actinoplanes teichomyceticus NRRL B-16726 is the only known producer of the clinically important glycopeptide antibiotic teicoplanin. The producing strain is highly self-resistant to teicoplanin. Although the biosynthesis of teicoplanin has been investigated, much of our understanding of self-resistance in the producing strain is based on the extrapolation of existing data about glycopeptide resistance (mediated by the expression of vanRS-vanHAX genes) in other actinomycetes and cocci. The organization of the operons carrying putative van orthologues in A. teichomyceticus differs from known precedents, further adding up to the uncertainty about teicoplanin self-resistance mechanisms. Here, we determined operon structure of the teicoplanin resistance genes in A. teichomyceticus. Although Tei15* is necessary to activate teicoplanin biosynthetic genes, the expression of van orthologues was shown to be independent of Tei15*. We further showed that tei7 promoter driving the expression of vanHAX orthologues is dependent on Tei2 (VanR). Finally, we demonstrate the utility of the tei2 promoter as a new tool to achieve strong constitutive expression in A. teichomyceticus.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2


  1. 1.

    Jovetic S, Zhu Y, Marcone GL, Marinelli F, Tramper J. β-lactam and glycopeptide antibiotics: first and last line of defense? Trends Biotechnol. 2010;28:596–604.

  2. 2.

    Nicolaou KC, Boddy CN, Bräse S, Winssinger N. Chemistry, biology, and medicine of the glycopeptide antibiotics. Angew Chem Int Ed Engl. 1999;38:2096–152.

  3. 3.

    Marcone GL, Binda E, Berini F, Marinelli F. Old and new glycopeptide antibiotics: from product to gene and back in the post-genomic era. Biotechnol Adv. 2018;36:534–54.

  4. 4.

    Pootoolal J, Neu J, Wright GD. Glycopeptide antibiotic resistance. Annu Rev Pharm Toxicol. 2002;42:381–408.

  5. 5.

    Koteva K, Hong HJ, Wang XD, Nazi I, Hughes D, Naldrett MJ, et al. A vancomycin photoprobe identifies the histidine kinase VanSsc as a vancomycin receptor. Nat Chem Biol. 2010;6:327–9.

  6. 6.

    Hughes CS, Longo E, Phillips-Jones MK, Hussain R. Characterization of the selective binding of antibiotics vancomycin and teicoplanin by the VanS receptor regulating type A vancomycin resistance in the enterococci. Biochim Biophys Acta Gen Subj. 2017;1861:1951–9.

  7. 7.

    Kwun MJ, Hong HJ. The activity of glycopeptide antibiotics against resistant bacteria correlates with their ability to induce the resistance system. Antimicrob Agents Chemother. 2014;58:6306–10.

  8. 8.

    Binda E, Cappelletti P, Marinelli F, Marcone GL. Specificity of induction of glycopeptide antibiotic resistance in the producing actinomycetes. Antibiotics. 2018;7:36.

  9. 9.

    Beltrametti F, Consolandi A, Carrano L, Bagatin F, Rossi R, Leoni L, et al. Resistance to glycopeptide antibiotics in the teicoplanin producer is mediated by van gene homologue expression directing the synthesis of a modified cell wall peptidoglycan. Antimicrob Agents Chemother. 2007;51:1135–41.

  10. 10.

    Yushchuk O, Horbal L, Ostash B, Marinelli F, Wohlleben W, Stegmann E, et al. Regulation of teicoplanin biosynthesis: refining the roles of tei cluster-situated regulatory genes. Appl Microbiol Biotechnol. 2019;103:4089–102.

  11. 11.

    Horbal L, Kobylyanskyy A, Truman AW, Zaburranyi N, Ostash B, Luzhetskyy A, et al. The pathway-specific regulatory genes, tei15* and tei16*, are the master switches of teicoplanin production in Actinoplanes teichomyceticus. Appl Microbiol Biotechnol. 2014;98:9295–309.

  12. 12.

    Horbal L, Kobylyanskyy A, Yushchuk O, Zaburannyi N, Luzhetskyy A, Ostash B, et al. Evaluation of heterologous promoters for genetic analysis of Actinoplanes teichomyceticus—producer of teicoplanin, drug of last defense. J Biotechnol.2013;168:367–72.

  13. 13.

    Kieser T, Bibb MJ, Buttner MJ, Chater KF, Hopwood DA. Practical Sreptomyces genetics. Norwich: John Innes Foundation; 2000.

  14. 14.

    Taurino C, Frattini L, Marcone GL, Gastaldo L, Marinelli F. Actinoplanes teichomyceticus ATCC 31121 as a cell factory for producing teicoplanin. Micro Cell Fact. 2011;10:82.

  15. 15.

    Myronovskyi M, Welle E, Fedorenko V, Luzhetskyy A. β-glucuronidase as a sensitive and versatile reporter in actinomycetes. Appl Environ Microbiol. 2011;77:5370–83.

  16. 16.

    Gregory MA, Till R, Smith MC. Integration site for Streptomyces phage φBT1 and development of site-specific integrating vectors. J Bacteriol. 2003;185:5320–3.

  17. 17.

    Li TL, Huang F, Haydock SF, Mironenko T, Leadlay PF, Spencer JB. Biosynthetic gene cluster of the glycopeptide antibiotic teicoplanin: characterization of two glycosyltransferases and the key acyltransferase. Chem Biol. 2004;11:107–19.

  18. 18.

    Zaburannyi N, Rabyk M, Ostash B, Fedorenko V, Luzhetskyy A. Insights into naturally minimised Streptomyces albus J1074 genome. BMC Genomics. 2014;15:97.

  19. 19.

    Hutchings MI, Hong HJ, Buttner MJ. The vancomycin resistance VanRS two-component signal transduction system of Streptomyces coelicolor. Mol Microbiol. 2006;59:923–35.

  20. 20.

    Koshla O, Yushchuk O, Ostash I, Dacyuk Y, Myronovskyi M, Jäger G, et al. Gene miaA for post-transcriptional modification of tRNA inferior is important for morphological and metabolic differentiation in Streptomyces. Mol Microbiol.2019;112:249–65.

Download references


We thank Prof. Margaret Smith for providing us with pMS82 vector. This work was supported by grant Bg-46F from the Ministry of Education and Science of Ukraine (to VF).

Author information

Correspondence to Victor Fedorenko.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yushchuk, O., Homoniuk, V., Ostash, B. et al. Genetic insights into the mechanism of teicoplanin self-resistance in Actinoplanes teichomyceticus. J Antibiot (2020).

Download citation

Further reading