Skip to main content
SpringerLink
Log in

Engineering Artificial Biodiversity of Lantibiotics to Expand Chemical Space of DNA-Encoded Antibiotics

  • REVIEW
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The discovery of antibiotics was one of the fundamental stages in the development of humanity, leading to a dramatic increase in the life expectancy of millions of people all over the world. The uncontrolled use of antibiotics resulted in the selection of resistant strains of bacteria, limiting the effectiveness of antimicrobial therapy nowadays. Antimicrobial peptides (AMPs) were considered promising candidates for next-generation antibiotics for a long time. However, the practical application of AMPs is restricted by their low therapeutic indices, impaired pharmacokinetics, and pharmacodynamics, which is predetermined by their peptide structure. Nevertheless, the DNA-encoded nature of AMPs enables creating broad repertoires of artificial biodiversity of antibiotics, making them versatile templates for the directed evolution of antibiotic activity. Lantibiotics are a unique class of AMPs with an expanded chemical space. A variety of post-translational modifications, mechanisms of action on bacterial membranes, and DNA-encoded nature make them a convenient molecular template for creating highly representative libraries of antimicrobial compounds. Isolation of new drug candidates from this synthetic biodiversity is extremely attractive but requires high-throughput screening of antibiotic activity. The combination of synthetic biology and ultrahigh-throughput microfluidics allows implementing the concept of directed evolution of lantibiotics for accelerated creation of new promising drug candidates.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.
Fig. 7.
Fig. 8.

Similar content being viewed by others

Abbreviations

AMP:

antimicrobial peptides

Dha:

dehydroalanine

Dhb:

dehydrobutyrine

PE:

phosphatidylethanolamine

RiPPs:

ribosomally synthesized and post-translationally modified peptides

UEV domain:

ubiquitin E2 variant domain

REFERENCES

  1. Davies, J., and Davies, D. (2010) Origins and evolution of antibiotic resistance, Microbiol. Mol. Biol. Rev., 74, 417-433, doi: https://doi.org/10.1128/mmbr.00016-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. O’Neill, J. (2014) Antimicrobial Resistance: Tackling A Crisis For The Health And Wealth Of Nations, Review on Antimicrobial Resistance, London.

  3. Czepiel, J., Drozdz, M., Pituch, H., Kuijper, E. J., Perucki, W., et al. (2019) Clostridium difficile infection: review, Eur. J. Clin. Microbiol. Infect. Dis., 38, 1211-1221, doi: https://doi.org/10.1007/s10096-019-03539-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang, J., Xiong, Z., Meng, H., Wang, Y., and Wang, Y. (2012) Synthetic biology triggers new era of antibiotics development, Subcell. Biochem., 64, 95-114, doi: https://doi.org/10.1007/978-94-007-5055-5_5.

    Article  CAS  PubMed  Google Scholar 

  5. Foulston, L. (2019) Genome mining and prospects for antibiotic discovery, Curr. Opin. Microbiol., 51, 1-8, doi: https://doi.org/10.1016/j.mib.2019.01.001.

    Article  CAS  PubMed  Google Scholar 

  6. Terekhov, S. S., Smirnov, I. V., Malakhova, M. V., Samoilov, A. E., Manolov, A. I., et al. (2018) Ultrahigh-throughput functional profiling of microbiota communities, Proc. Natl. Acad. Sci. USA, 115, 9551-9556, doi: https://doi.org/10.1073/pnas.1811250115.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Stokes, J. M., Yang, K., Swanson, K., Jin, W., Cubillos-Ruiz, A., et al. (2020) A deep learning approach to antibiotic discovery, Cell, 180, 688-702, doi: https://doi.org/10.1016/j.cell.2020.01.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lau, J. L., and Dunn, M. K. (2018) Therapeutic peptides: historical perspectives, current development trends, and future directions, Bioorg. Med. Chem., 26, 2700-2707, doi: https://doi.org/10.1016/j.bmc.2017.06.052.

    Article  CAS  PubMed  Google Scholar 

  9. Fosgerau, K., and Hoffmann, T. (2015) Peptide therapeutics: current status and future directions, Drug Discov. Today, 20, 122-128, doi: https://doi.org/10.1016/j.drudis.2014.10.003.

    Article  CAS  PubMed  Google Scholar 

  10. Lei, J., Sun, L., Huang, S., Zhu, C., Li, P., et al. (2019) The antimicrobial peptides and their potential clinical applications, Am. J. Transl. Res., 11, 3919-3931.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Kang, S. J., Park, S. J., Mishig-Ochir, T., and Lee, B. J. (2014) Antimicrobial peptides: therapeutic potentials, Expert. Rev. Anti. Infect. Ther., 12, 1477-1486, doi: https://doi.org/10.1586/14787210.2014.976613.

    Article  CAS  PubMed  Google Scholar 

  12. Ortega, M. A., and van der Donk, W. A. (2016) New insights into the biosynthetic logic of ribosomally synthesized and post-translationally modified peptide natural products, Cell Chem. Biol., 23, 31-44, doi: https://doi.org/10.1016/j.chembiol.2015.11.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McIntosh, J. A., Donia, M. S., and Schmidt, E. W. (2009) Ribosomal peptide natural products: bridging the ribosomal and nonribosomal worlds, Nat. Prod. Rep., 26, 537-559, doi: https://doi.org/10.1039/b714132g.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Muller, M. M. (2018) Post-translational modifications of protein backbones: unique functions, mechanisms, and challenges, Biochemistry, 57, 177-185, doi: https://doi.org/10.1021/acs.biochem.7b00861.

    Article  CAS  PubMed  Google Scholar 

  15. Hudson, G. A., and Mitchell, D. A. (2018) RiPP antibiotics: biosynthesis and engineering potential, Curr. Opin. Microbiol., 45, 61-69, doi: https://doi.org/10.1016/j.mib.2018.02.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mullane, K., Lee, C., Bressler, A., Buitrago, M., Weiss, K., et al. (2015) Multicenter, randomized clinical trial to compare the safety and efficacy of LFF571 and vancomycin for Clostridium difficile infections, Antimicrob. Agents Chemother., 59, 1435-1440, doi: https://doi.org/10.1128/aac.04251-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Poorinmohammad, N., Bagheban-Shemirani, R., and Hamedi, J. (2019) Genome mining for ribosomally synthesised and post-translationally modified peptides (RiPPs) reveals undiscovered bioactive potentials of actinobacteria, Antonie Van Leeuwenhoek, 112, 1477-1499, doi: https://doi.org/10.1007/s10482-019-01276-6.

    Article  CAS  PubMed  Google Scholar 

  18. Velasquez, J. E., and van der Donk, W. A. (2011) Genome mining for ribosomally synthesized natural products, Curr. Opin. Chem. Biol., 15, 11-21, doi: https://doi.org/10.1016/j.cbpa.2010.10.027.

    Article  CAS  PubMed  Google Scholar 

  19. Arnison, P. G., Bibb, M. J., Bierbaum, G., Bowers, A. A., Bugni, T. S., et al. (2013) Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature, Nat. Prod. Rep., 30, 108-160, doi: https://doi.org/10.1039/C2NP20085F.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Repka, L. M., Chekan, J. R., Nair, S. K., and van der Donk, W. A. (2017) Mechanistic understanding of lanthipeptide biosynthetic enzymes, Chem. Rev., 117, 5457-5520, doi: https://doi.org/10.1021/acs.chemrev.6b00591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kleerebezem, M. (2004) Quorum sensing control of lantibiotic production; nisin and subtilin autoregulate their own biosynthesis, Peptides, 25, 1405-1414, doi: https://doi.org/10.1016/j.peptides.2003.10.021.

    Article  CAS  PubMed  Google Scholar 

  22. Willey, J. M., Willems, A., Kodani, S., and Nodwell, J. R. (2006) Morphogenetic surfactants and their role in the formation of aerial hyphae in Streptomyces coelicolor, Mol. Microbiol., 59, 731-742, doi: https://doi.org/10.1111/j.1365-2958.2005.05018.x.

    Article  CAS  PubMed  Google Scholar 

  23. Bierbaum, G., Gotz, F., Peschel, A., Kupke, T., van de Kamp, M., and Sahl, H. G. (1996) The biosynthesis of the lantibiotics epidermin, gallidermin, Pep5 and epilancin K7, Antonie Van Leeuwenhoek, 69, 119-127, doi: https://doi.org/10.1007/BF00399417.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang, Q., Yu, Y., Velasquez, J. E., and van der Donk, W. A. (2012) Evolution of lanthipeptide synthetases, Proc. Natl. Acad. Sci. USA, 109, 18361-18366, doi: https://doi.org/10.1073/pnas.1210393109.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shi, Y., Yang, X., Garg, N., and van der Donk, W. A. (2011) Production of lantipeptides in Escherichia coli, J. Am. Chem. Soc., 133, 2338-2341, doi: https://doi.org/10.1021/ja109044r.

    Article  CAS  PubMed  Google Scholar 

  26. Garg, N., Salazar-Ocampo, L. M., and van der Donk, W. A. (2013) In vitro activity of the nisin dehydratase NisB, Proc. Natl. Acad. Sci. USA, 110, 7258-7263, doi: https://doi.org/10.1073/pnas.1222488110.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ortega, M. A., Hao, Y., Zhang, Q., Walker, M. C., van der Donk, W. A., and Nair, S. K. (2015) Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB, Nature, 517, 509-512, doi: https://doi.org/10.1038/nature13888.

    Article  CAS  PubMed  Google Scholar 

  28. Siezen, R. J., Kuipers, O. P., and de Vos, W. M. (1996) Comparison of lantibiotic gene clusters and encoded proteins, Antonie Van Leeuwenhoek, 69, 171-184, doi: https://doi.org/10.1007/BF00399422.

    Article  CAS  PubMed  Google Scholar 

  29. Goto, Y., Okesli, A., and van der Donk, W. A. (2011) Mechanistic studies of Ser/Thr dehydration catalyzed by a member of the LanL lanthionine synthetase family, Biochemistry, 50, 891-898, doi: https://doi.org/10.1021/bi101750r.

    Article  CAS  PubMed  Google Scholar 

  30. Hollenstein, K., Dawson, R. J., and Locher, K. P. (2007) Structure and mechanism of ABC transporter proteins, Curr. Opin. Struct. Biol., 17, 412-418, doi: https://doi.org/10.1016/j.sbi.2007.07.003.

    Article  CAS  PubMed  Google Scholar 

  31. Kuipers, A., de Boef, E., Rink, R., Fekken, S., Kluskens, L. D., et al. (2004) NisT, the transporter of the lantibiotic nisin, can transport fully modified, dehydrated, and unmodified prenisin and fusions of the leader peptide with non-lantibiotic peptides, J. Biol. Chem., 279, 22176-22182, doi: https://doi.org/10.1074/jbc.M312789200.

    Article  CAS  PubMed  Google Scholar 

  32. Lagedroste, M., Smits, S. H. J., and Schmitt, L. (2017) Substrate specificity of the secreted nisin leader peptidase NisP, Biochemistry, 56, 4005-4014, doi: https://doi.org/10.1021/acs.biochem.7b00524.

    Article  CAS  PubMed  Google Scholar 

  33. Velasquez, J. E., Zhang, X., and van der Donk, W. A. (2011) Biosynthesis of the antimicrobial peptide epilancin 15X and its N-terminal lactate, Chem. Biol., 18, 857-867, doi: https://doi.org/10.1016/j.chembiol.2011.05.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Huang, E., and Yousef, A. E. (2015) Biosynthesis of paenibacillin, a lantibiotic with N-terminal acetylation, by Paenibacillus polymyxa, Microbiol. Res., 181, 15-21, doi: https://doi.org/10.1016/j.micres.2015.08.001.

    Article  CAS  PubMed  Google Scholar 

  35. Allgaier, H., Jung, G., Werner, R. G., Schneider, U., and Zähner, H. (1985) Elucidation of the structure of epidermin, a ribosomally synthesized, tetracyclic heterodetic polypeptide antibiotic, Angew. Chem. Internat. Ed. Engl., 24, 1051-1053, doi: https://doi.org/10.1002/anie.198510511.

    Article  Google Scholar 

  36. De Arauz, L. J., Jozala, A. F., Mazzola, P. G., and Vessoni Penna, T. C. (2009) Nisin biotechnological production and application: a review, Trends Food Sci. Technol., 20, 146-154, doi: https://doi.org/10.1016/j.tifs.2009.01.056.

    Article  CAS  Google Scholar 

  37. Lepak, A. J., Marchillo, K., Craig, W. A., and Andes, D. R. (2015) In vivo pharmacokinetics and pharmacodynamics of the lantibiotic NAI-107 in a neutropenic murine thigh infection model, Antimicrob. Agents Chemother., 59, 1258-1264, doi: https://doi.org/10.1128/AAC.04444-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Thomsen, T. T., Mojsoska, B., Cruz, J. C., Donadio, S., Jenssen, H., Lobner-Olesen, A., and Rewitz, K. (2016) The Lantibiotic NAI-107 efficiently rescues Drosophila melanogaster from infection with methicillin-resistant Staphylococcus aureus USA300, Antimicrob. Agents Chemother., 60, 5427-5436, doi: https://doi.org/10.1128/AAC.02965-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Castiglione, F., Lazzarini, A., Carrano, L., Corti, E., Ciciliato, I., et al. (2008) Determining the structure and mode of action of microbisporicin, a potent lantibiotic active against multiresistant pathogens, Chem. Biol., 15, 22-31, doi: https://doi.org/10.1016/j.chembiol.2007.11.009.

    Article  CAS  PubMed  Google Scholar 

  40. Chatterjee, C., Miller, L. M., Leung, Y. L., Xie, L., Yi, M., Kelleher, N. L., and van der Donk, W. A. (2005) Lacticin 481 synthetase phosphorylates its substrate during lantibiotic production, J. Am. Chem. Soc., 127, 15332-15333, doi: https://doi.org/10.1021/ja0543043.

    Article  CAS  PubMed  Google Scholar 

  41. Dong, S. H., Tang, W., Lukk, T., Yu, Y., Nair, S. K., and van der Donk, W. A. (2015) The enterococcal cytolysin synthetase has an unanticipated lipid kinase fold, eLife, 4, e07607, doi: https://doi.org/10.7554/eLife.07607.

    Article  PubMed Central  Google Scholar 

  42. Ma, H., Gao, Y., Zhao, F., and Zhong, J. (2015) Individual catalytic activity of two functional domains of bovicin HJ50 synthase BovM, Wei Sheng Wu Xue Bao, 55, 50-58.

    CAS  PubMed  Google Scholar 

  43. Shimafuji, C., Noguchi, M., Nishie, M., Nagao, J., Shioya, K., Zendo, T., Nakayama, J., and Sonomoto, K. (2015) In vitro catalytic activity of N-terminal and C-terminal domains in NukM, the post-translational modification enzyme of nukacin ISK-1, J. Biosci. Bioeng., 120, 624-629, doi: https://doi.org/10.1016/j.jbiosc.2015.03.020.

    Article  CAS  PubMed  Google Scholar 

  44. Tang, W., Jimenez-Oses, G., Houk, K. N., and van der Donk, W. A. (2015) Substrate control in stereoselective lanthionine biosynthesis, Nat. Chem., 7, 57-64, doi: https://doi.org/10.1038/nchem.2113.

    Article  CAS  PubMed  Google Scholar 

  45. Thibodeaux, C. J., Ha, T., and van der Donk, W. A. (2014) A price to pay for relaxed substrate specificity: a comparative kinetic analysis of the class II lanthipeptide synthetases ProcM and HalM2, J. Am. Chem. Soc., 136, 17513-17529, doi: https://doi.org/10.1021/ja5089452.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cubillos-Ruiz, A., Berta-Thompson, J. W., Becker, J. W., van der Donk, W. A., and Chisholm, S. W. (2017) Evolutionary radiation of lanthipeptides in marine cyanobacteria, Proc. Natl. Acad. Sci. USA, 114, E5424-E5433, doi: https://doi.org/10.1073/pnas.1700990114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nishie, M., Sasaki, M., Nagao, J., Zendo, T., Nakayama, J., and Sonomoto, K. (2011) Lantibiotic transporter requires cooperative functioning of the peptidase domain and the ATP binding domain, J. Biol. Chem., 286, 11163-11169, doi: https://doi.org/10.1074/jbc.M110.212704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kuipers, A., Meijer-Wierenga, J., Rink, R., Kluskens, L. D., and Moll, G. N. (2008) Mechanistic dissection of the enzyme complexes involved in biosynthesis of lacticin 3147 and nisin, Appl. Environ. Microbiol., 74, 6591-6597, doi: https://doi.org/10.1128/AEM.01334-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Caetano, T., Barbosa, J., Moesker, E., Sussmuth, R. D., and Mendo, S. (2014) Bioengineering of lanthipeptides in Escherichia coli: assessing the specificity of lichenicidin and haloduracin biosynthetic machinery, Res. Microbiol., 165, 600-604, doi: https://doi.org/10.1016/j.resmic.2014.07.006.

    Article  CAS  PubMed  Google Scholar 

  50. Galvin, M., Hill, C., and Ross, R. P. (1999) Lacticin 3147 displays activity in buffer against gram-positive bacterial pathogens which appear insensitive in standard plate assays, Lett. Appl. Microbiol., 28, 355-358, doi: https://doi.org/10.1046/j.1365-2672.1999.00550.x.

    Article  CAS  PubMed  Google Scholar 

  51. Oman, T. J., and van der Donk, W. A. (2009) Insights into the mode of action of the two-peptide lantibiotic haloduracin, ACS Chem. Biol., 4, 865-874, doi: https://doi.org/10.1021/cb900194x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xin, B., Zheng, J., Xu, Z., Li, C., Ruan, L., Peng, D., and Sun, M. (2015) Three novel lantibiotics, ticins A1, A3, and A4, have extremely stable properties and are promising food biopreservatives, Appl. Environ. Microbiol., 81, 6964-6972, doi: https://doi.org/10.1128/aem.01851-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Crowther, G. S., Baines, S. D., Todhunter, S. L., Freeman, J., Chilton, C. H., and Wilcox, M. H. (2013) Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection, J. Antimicrob. Chemother., 68, 168-176, doi: https://doi.org/10.1093/jac/dks359.

    Article  CAS  PubMed  Google Scholar 

  54. Louie, T. J., Emery, J., Krulicki, W., Byrne, B., and Mah, M. (2009) OPT-80 eliminates Clostridium difficile and is sparing of bacteroides species during treatment of C. difficile Infection, Antimicrob. Agents Chemother., 53, 261-263, doi: https://doi.org/10.1128/aac.01443-07.

    Article  CAS  PubMed  Google Scholar 

  55. Knerr, P. J., and van der Donk, W. A. (2012) Discovery, biosynthesis, and engineering of lantipeptides, Annu. Rev. Biochem., 81, 479-505, doi: https://doi.org/10.1146/annurev-biochem-060110-113521.

    Article  CAS  PubMed  Google Scholar 

  56. Kodani, S., Hudson, M. E., Durrant, M. C., Buttner, M. J., Nodwell, J. R., and Willey, J. M. (2004) The SapB morphogen is a lantibiotic-like peptide derived from the product of the developmental gene ramS in Streptomyces coelicolor, Proc. Natl. Acad. Sci. USA, 101, 11448-11453, doi: https://doi.org/10.1073/pnas.0404220101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Meindl, K., Schmiederer, T., Schneider, K., Reicke, A., Butz, D., et al. (2010) Labyrinthopeptins: a new class of carbacyclic lantibiotics, Angew. Chem. Int. Ed. Engl., 49, 1151-1154, doi: https://doi.org/10.1002/anie.200905773.

    Article  CAS  PubMed  Google Scholar 

  58. Krawczyk, B., Ensle, P., Müller, W. M., and Süssmuth, R. D. (2012) Deuterium labeled peptides give insights into the directionality of class III lantibiotic synthetase LabKC, J. Am. Chem. Soc., 134, 9922-9925, doi: https://doi.org/10.1021/ja3040224.

    Article  CAS  PubMed  Google Scholar 

  59. Müller, W. M., Schmiederer, T., Ensle, P., and Süssmuth, R. D. (2010) In vitro biosynthesis of the prepeptide of type-III lantibiotic labyrinthopeptin A2 including formation of a C-C bond as a post-translational modification, Angew. Chem. Int. Ed. Engl., 49, 2436-2440, doi: https://doi.org/10.1002/anie.200905909.

    Article  CAS  PubMed  Google Scholar 

  60. Völler, G. H., Krawczyk, J. M., Pesic, A., Krawczyk, B., Nachtigall, J., and Süssmuth, R. D. (2012) Characterization of new class III lantibiotics–erythreapeptin, avermipeptin and griseopeptin from Saccharopolyspora erythraea, Streptomyces avermitilis and Streptomyces griseus demonstrates stepwise N-terminal leader processing, Chembiochem, 13, 1174-1183, doi: https://doi.org/10.1002/cbic.201200118.

    Article  CAS  PubMed  Google Scholar 

  61. Iorio, M., Sasso, O., Maffioli, S. I., Bertorelli, R., Monciardini, P., et al. (2014) A glycosylated, labionin-containing lanthipeptide with marked antinociceptive activity, ACS Chem. Biol., 9, 398-404, doi: https://doi.org/10.1021/cb400692w.

    Article  CAS  PubMed  Google Scholar 

  62. Chen, S., Xu, B., Chen, E., Wang, J., Lu, J., Donadio, S., Ge, H., and Wang, H. (2019) Zn-dependent bifunctional proteases are responsible for leader peptide processing of class III lanthipeptides, Proc. Natl. Acad. Sci. USA, 116, 2533-2538, doi: https://doi.org/10.1073/pnas.1815594116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kodani, S., Lodato, M. A., Durrant, M. C., Picart, F., and Willey, J. M. (2005) SapT, a lanthionine-containing peptide involved in aerial hyphae formation in the streptomycetes, Mol. Microbiol., 58, 1368-1380, doi: https://doi.org/10.1111/j.1365-2958.2005.04921.x.

    Article  CAS  PubMed  Google Scholar 

  64. Ferir, G., Petrova, M. I., Andrei, G., Huskens, D., Hoorelbeke, B., et al. (2013) The lantibiotic peptide labyrinthopeptin A1 demonstrates broad anti-HIV and anti-HSV activity with potential for microbicidal applications, PLoS One, 8, e64010, doi: https://doi.org/10.1371/journal.pone.0064010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Goto, Y., Li, B., Claesen, J., Shi, Y., Bibb, M. J., and van der Donk, W. A. (2010) Discovery of unique lanthionine synthetases reveals new mechanistic and evolutionary insights, PLoS Biol., 8, e1000339, doi: https://doi.org/10.1371/journal.pbio.1000339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhang, Q., Doroghazi, J. R., Zhao, X., Walker, M. C., and van der Donk, W. A. (2015) Expanded natural product diversity revealed by analysis of lanthipeptide-like gene clusters in actinobacteria, Appl. Environ. Microbiol., 81, 4339-4350, doi: https://doi.org/10.1128/AEM.00635-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Iftime, D., Jasyk, M., Kulik, A., Imhoff, J. F., Stegmann, E., Wohlleben, W., Süssmuth, R. D., and Weber, T. (2015) Streptocollin, a type IV lanthipeptide produced by Streptomyces collinus Tü 365, Chembiochem., 16, 2615-2623, doi: https://doi.org/10.1002/cbic.201500377.

    Article  CAS  PubMed  Google Scholar 

  68. Hegemann, J. D., and van der Donk, W. A. (2018) Investigation of substrate recognition and biosynthesis in class IV lanthipeptide systems, J. Am. Chem. Soc., 140, 5743-5754, doi: https://doi.org/10.1021/jacs.8b01323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rogers, L. A. (1928) The inhibiting effect of Streptococcus Lactis on Lactobacillus Bulgaricus, J. Bacteriol., 16, 321-325, doi: https://doi.org/10.1128/JB.16.5.321-325.1928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mattick, A. T. R., Hirsch, A., and Berridge, N. J. (1947) Further observations on an inhibitory substance (nisin) from lactic streptococci, Lancet, 250, 5-8, doi: https://doi.org/10.1016/S0140-6736(47)90004-4.

    Article  Google Scholar 

  71. Van Heijenoort, Y., Gomez, M., Derrien, M., Ayala, J., and van Heijenoort, J. (1992) Membrane intermediates in the peptidoglycan metabolism of Escherichia coli: possible roles of PBP 1b and PBP 3, J. Bacteriol., 174, 3549-3557, doi: https://doi.org/10.1128/jb.174.11.3549-3557.1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Breukink, E., and de Kruijff, B. (2006) Lipid II as a target for antibiotics, Nat. Rev. Drug Discov., 5, 321-323, doi: https://doi.org/10.1038/nrd2004.

    Article  CAS  PubMed  Google Scholar 

  73. Piper, C., Draper, L. A., Cotter, P. D., Ross, R. P., and Hill, C. (2009) A comparison of the activities of lacticin 3147 and nisin against drug-resistant Staphylococcus aureus and Enterococcus species, J. Antimicrob. Chemother., 64, 546-551, doi: https://doi.org/10.1093/jac/dkp221.

    Article  CAS  PubMed  Google Scholar 

  74. Dischinger, J., Basi Chipalu, S., and Bierbaum, G. (2014) Lantibiotics: promising candidates for future applications in health care, Int. J. Med. Microbiol., 304, 51-62, doi: https://doi.org/10.1016/j.ijmm.2013.09.003.

    Article  CAS  PubMed  Google Scholar 

  75. Hsu, S.-T. D., Breukink, E., Tischenko, E., Lutters, M. A. G., de Kruijff, B., et al. (2004) The nisin–lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics, Nat. Struct. Mol. Biol., 11, 963-967, doi: https://doi.org/10.1038/nsmb830.

    Article  CAS  PubMed  Google Scholar 

  76. Hasper, H. E., de Kruijff, B., and Breukink, E. (2004) Assembly and stability of nisin-lipid II pores, Biochemistry, 43, 11567-11575, doi: https://doi.org/10.1021/bi049476b.

    Article  CAS  PubMed  Google Scholar 

  77. Märki, F., Hänni, E., Fredenhagen, A., and van Oostrum, J. (1991) Mode of action of the lanthionine-containing peptide antibiotics duramycin, duramycin B and C, and cinnamycin as indirect inhibitors of phospholipase A2, Biochem. Pharmacol., 42, 2027-2035, doi: https://doi.org/10.1016/0006-2952(91)90604-4.

    Article  PubMed  Google Scholar 

  78. Vance, J. E., and Tasseva, G. (2013) Formation and function of phosphatidylserine and phosphatidylethanolamine in mammalian cells, Biochim. Biophys. Acta, 1831, 543-554, doi: https://doi.org/10.1016/j.bbalip.2012.08.016.

    Article  CAS  PubMed  Google Scholar 

  79. Gbaguidi, B., Hakizimana, P., Vandenbussche, G., and Ruysschaert, J. M. (2007) Conformational changes in a bacterial multidrug transporter are phosphatidylethanolamine-dependent, Cell. Mol. Life Sci., 64, 1571-1582, doi: https://doi.org/10.1007/s00018-007-7031-0.

    Article  CAS  PubMed  Google Scholar 

  80. Epand, R. M., and Epand, R. F. (2009) Lipid domains in bacterial membranes and the action of antimicrobial agents, Biochim. Biophys. Acta, 1788, 289-294, doi: https://doi.org/10.1016/j.bbamem.2008.08.023.

    Article  CAS  PubMed  Google Scholar 

  81. Vestergaard, M., Berglund, N. A., Hsu, P. C., Song, C., Koldso, H., Schiott, B., and Sansom, M. S. P. (2019) Structure and dynamics of cinnamycin-lipid complexes: mechanisms of selectivity for phosphatidylethanolamine lipids, ACS Omega, 4, 18889-18899, doi: https://doi.org/10.1021/acsomega.9b02949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Choung, S. Y., Kobayashi, T., Takemoto, K., Ishitsuka, H., and Inoue, K. (1988) Interaction of a cyclic peptide, Ro09-0198, with phosphatidylethanolamine in liposomal membranes, Biochim. Biophys. Acta, 940, 180-187, doi: https://doi.org/10.1016/0005-2736(88)90193-9.

    Article  CAS  PubMed  Google Scholar 

  83. Hasim, S., Allison, D. P., Mendez, B., Farmer, A. T., Pelletier, D. A., Retterer, S. T., Campagna, S. R., Reynolds, T. B., and Doktycz, M. J. (2018) Elucidating duramycin’s bacterial selectivity and mode of action on the bacterial cell envelope, Front. Microbiol., 9, 219, doi: https://doi.org/10.3389/fmicb.2018.00219.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Jones, A. M., and Helm, J. M. (2009) Emerging treatments in cystic fibrosis, Drugs, 69, 1903-1910, doi: https://doi.org/10.2165/11318500-000000000-00000.

    Article  CAS  PubMed  Google Scholar 

  85. Elvas, F., Stroobants, S., and Wyffels, L. (2017) Phosphatidylethanolamine targeting for cell death imaging in early treatment response evaluation and disease diagnosis, Apoptosis, 22, 971-987, doi: https://doi.org/10.1007/s10495-017-1384-0.

    Article  CAS  PubMed  Google Scholar 

  86. Emoto, K., Kobayashi, T., Yamaji, A., Aizawa, H., Yahara, I., Inoue, K., and Umeda, M. (1996) Redistribution of phosphatidylethanolamine at the cleavage furrow of dividing cells during cytokinesis, Proc. Natl. Acad. Sci. USA, 93, 12867-12872, doi: https://doi.org/10.1073/pnas.93.23.12867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhao, M. (2011) Lantibiotics as probes for phosphatidylethanolamine, Amino Acids, 41, 1071-1079, doi: https://doi.org/10.1007/s00726-009-0386-9.

    Article  CAS  PubMed  Google Scholar 

  88. Hofmann, F. T., Szostak, J. W., and Seebeck, F. P. (2012) In vitro selection of functional lantipeptides, J. Am. Chem. Soc., 134, 8038-8041, doi: https://doi.org/10.1021/ja302082d.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Zhou, X. X., Li, W. F., Ma, G. X., and Pan, Y. J. (2006) The nisin-controlled gene expression system: construction, application and improvements, Biotechnol. Adv., 24, 285-295, doi: https://doi.org/10.1016/j.biotechadv.2005.11.001.

    Article  CAS  PubMed  Google Scholar 

  90. Aso, Y., Nagao, J.-I., Koga, H., Okuda, K.-I., Kanemasa, Y., Sashihara, T., Nakayama, J., and Sonomoto, K. (2004) Heterologous expression and functional analysis of the gene cluster for the biosynthesis of and immunity to the lantibiotic, nukacin ISK-1, J. Biosci. Bioeng., 98, 429-436, doi: https://doi.org/10.1016/S1389-1723(05)00308-7.

    Article  CAS  PubMed  Google Scholar 

  91. Böttiger, T., Schneider, T., Martínez, B., Sahl, H.-G., and Wiedemann, I. (2009) Influence of Ca2+ ions on the activity of lantibiotics containing a mersacidin-like lipid II binding motif, Appl. Environ. Microbiol., 75, 4427-4434, doi: https://doi.org/10.1128/aem.00262-09.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Li, Y. (2011) Recombinant production of antimicrobial peptides in Escherichia coli: a review, Protein Expr. Purif., 80, 260-267, doi: https://doi.org/10.1016/j.pep.2011.08.001.

    Article  CAS  PubMed  Google Scholar 

  93. Mesa-Pereira, B., Rea, M. C., Cotter, P. D., Hill, C., and Ross, R. P. (2018) Heterologous expression of biopreservative bacteriocins with a view to low cost production, Front. Microbiol., 9, 1654, doi: https://doi.org/10.3389/fmicb.2018.01654.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Si, T., Tian, Q., Min, Y., Zhang, L., Sweedler, J. V., van der Donk, W. A., and Zhao, H. (2018) Rapid screening of lanthipeptide analogs via in-colony removal of leader peptides in Escherichia coli, J. Am. Chem. Soc., 140, 11884-11888, doi: https://doi.org/10.1021/jacs.8b05544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Geng, M., and Smith, L. (2018) Modifying the lantibiotic mutacin 1140 for increased yield, activity, and stability, Appl. Environ. Microbiol., 84, doi: https://doi.org/10.1128/AEM.00830-18.

    Article  Google Scholar 

  96. Field, D., Connor, P. M., Cotter, P. D., Hill, C., and Ross, R. P. (2008) The generation of nisin variants with enhanced activity against specific gram-positive pathogens, Mol. Microbiol., 69, 218-230, doi: https://doi.org/10.1111/j.1365-2958.2008.06279.x.

    Article  CAS  PubMed  Google Scholar 

  97. Yoganathan, S., Sit, C. S., and Vederas, J. C. (2011) Chemical synthesis and biological evaluation of gallidermin-siderophore conjugates, Org. Biomol. Chem., 9, 2133-2141, doi: https://doi.org/10.1039/c0ob00846j.

    Article  CAS  PubMed  Google Scholar 

  98. Li, Q., Montalban-Lopez, M., and Kuipers, O. P. (2018) Increasing the antimicrobial activity of nisin-based lantibiotics against Gram-negative pathogens, Appl. Environ. Microbiol., 84, doi: https://doi.org/10.1128/AEM.00052-18.

    Google Scholar 

  99. Yang, X., Lennard, K. R., He, C., Walker, M. C., Ball, A. T., Doigneaux, C., Tavassoli, A., and van der Donk, W. A. (2018) A lanthipeptide library used to identify a protein–protein interaction inhibitor, Nat. Chem. Biol., 14, 375-380, doi: https://doi.org/10.1038/s41589-018-0008-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Nixon, A. E., Sexton, D. J., and Ladner, R. C. (2014) Drugs derived from phage display: from candidate identification to clinical practice, MAbs, 6, 73-85, doi: https://doi.org/10.4161/mabs.27240.

    Article  PubMed  Google Scholar 

  101. Urban, J. H., Moosmeier, M. A., Aumuller, T., Thein, M., Bosma, T., et al. (2017) Phage display and selection of lanthipeptides on the carboxy-terminus of the gene-3 minor coat protein, Nat. Commun., 8, 1500, doi: https://doi.org/10.1038/s41467-017-01413-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hetrick, K. J., Walker, M. C., and van der Donk, W. A. (2018) Development and application of yeast and phage display of diverse lanthipeptides, ACS Cent. Sci., 4, 458-467, doi: https://doi.org/10.1021/acscentsci.7b00581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Convery, N., and Gadegaard, N. (2019) 30 years of microfluidics, Micro Nano Eng., 2, 76-91, doi: https://doi.org/10.1016/j.mne.2019.01.003.

    Article  Google Scholar 

  104. Fallah-Araghi, A., Baret, J. C., Ryckelynck, M., and Griffiths, A. D. (2012) A completely in vitro ultrahigh-throughput droplet-based microfluidic screening system for protein engineering and directed evolution, Lab. Chip., 12, 882-891, doi: https://doi.org/10.1039/c2lc21035e.

    Article  CAS  PubMed  Google Scholar 

  105. Mahler, L., Wink, K., Beulig, R. J., Scherlach, K., Tovar, M., et al. (2018) Detection of antibiotics synthetized in microfluidic picolitre-droplets by various actinobacteria, Sci. Rep., 8, 13087, doi: https://doi.org/10.1038/s41598-018-31263-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Terekhov, S. S., Smirnov, I. V., Stepanova, A. V., Bobik, T. V., Mokrushina, Y. A., et al. (2017) Microfluidic droplet platform for ultrahigh-throughput single-cell screening of biodiversity, Proc. Natl. Acad. Sci. USA, 114, 2550-2555, doi: https://doi.org/10.1073/pnas.1621226114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The research was financially supported by the Russian Foundation for Basic Research (project no. 18-29-08054) and by the Russian Science Foundation (project no. 17-74-30019).

Author information

Authors and Affiliations

  1. Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997, Moscow, Russia

    S. O. Pipiya, S. S. Terekhov, Yu. A. Mokrushina, V. D. Knorre, I. V. Smirnov & A. G. Gabibov

  2. Faculty of Chemistry, Lomonosov Moscow State University, 119991, Moscow, Russia

    S. S. Terekhov, Yu. A. Mokrushina, I. V. Smirnov & A. G. Gabibov

Authors
  1. S. O. Pipiya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. S. Terekhov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu. A. Mokrushina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V. D. Knorre
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I. V. Smirnov
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. G. Gabibov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. V. Smirnov.

Ethics declarations

The authors declare no conflicts of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pipiya, S.O., Terekhov, S.S., Mokrushina, Y.A. et al. Engineering Artificial Biodiversity of Lantibiotics to Expand Chemical Space of DNA-Encoded Antibiotics. Biochemistry Moscow 85, 1319–1334 (2020). https://doi.org/10.1134/S0006297920110048

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920110048

Keywords

Search

Navigation