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Ficellomycin: an aziridine alkaloid antibiotic with potential therapeutic capacity

Abstract

Ficellomycin is an aziridine antibiotic produced by Streptomyces ficellus, which displays high in vitro activity against Gram-positive bacteria including multidrug resistant strains of Staphylococcus aureus. Compared to currently available antibiotics, ficellomycin exhibits a unique mechanism of action—it impairs the semiconservative DNA replication by inducing the formation of deficient 34S DNA fragments, which lack the ability to integrate into larger DNA pieces and eventually the complete bacterial chromosome. Until recently, some important progress has been made in research on ficellomycin synthesis and biosynthesis, opening the perspective to develop a new generation of antibiotics with better clinical performance than the currently used ones. In this review, we will cover the discovery and biological activity of ficellomycin, its biosynthesis, mode of action, and related synthetic analogs. The role of ficellomycin and its analogs as an important source of drug prototypes will be discussed together with future research prospects.

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References

  • Argoudelis AD, Reusser F, Whaley HA, Baczynskyj L, Mizsak SA, Wnuk RJ (1976) Antibiotics produced by Streptomyces ficellus. I. Ficellomycin. J Antibiot 29(10):1001–1006

    Article  PubMed  CAS  Google Scholar 

  • Ashburn T, Thor K (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3(8):673–683

    Article  PubMed  CAS  Google Scholar 

  • Bicker U, Fischer W (1974) Enzymatic aziridine synthesis from beta amino-alcohols—a new example of endogenous carcinogen formation. Nature 455:344–345

    Article  Google Scholar 

  • Brandt A, Gardner M (2003) Companion to medicine in the twentieth century. Routledge, Abingdon

    Google Scholar 

  • Brulikova L, Hlavac J, Hradil P (2012) DNA interstrand cross-linking agents and their chemotherapeutic potential. Curr Med Chem 19(3):364–385

    Article  PubMed  CAS  Google Scholar 

  • Bush K (2010) The coming age of antibiotics: discovery and therapeutic value. Ann. N.Y. Acad Sci 1213:1–4

    Article  PubMed  Google Scholar 

  • Chen G, He Z, Yu A (2014) Synthesis of functionalized 1-azabicyclo[3.1.0]hexanes: studies towards ficellomycin and its analogs. Hetercycles 88:1299–1309

    Article  CAS  Google Scholar 

  • Drusano G, Hope W, MacGowan A, Louie A (2015) Suppression of emergence of resistance in pathogenic bacteria: keeping our powder dry, part 2. Antimicrob Agents Chemother 60(3):1194–1201

    Article  PubMed  CAS  Google Scholar 

  • Foulke-Abel J, Agbo H, Zhang H, Mori S, Watanabe CM (2011) Mode of action and biosynthesis of the azabicycle-containing natural products azinomycin and ficellomycin. Nat Prod Rep 4:693–704

    Article  CAS  Google Scholar 

  • Frances M, William E, Charlesnika T, Michael Y, William A, Mai T, Susan C, Kathleen M, Stuart J, Monica K, Lance R, Anthony E, Dale N (2017) The impact of recurrent clostridium difficile infection on patients’ prevention behaviors. Infect Control Hosp Epidemiol 38:1351–1357. https://doi.org/10.1017/ice.2017.208

    Article  Google Scholar 

  • Gracia M (2007) Torwards the total synthesis of ficellomycin. dissertation, University of Warwick. UK

  • Haaber J, Penadés J, Ingmer H (2017) Transfer of antibiotic resistance in Staphylococcus aureus. Trends Microbiol 25(11):893–905

    Article  PubMed  CAS  Google Scholar 

  • Imae K, Kamachi H, Yamashita H, Okita T, Okuyama S, Tsuno T, Yamasaki T, Sawada Y, Ohbayashi M, Naito T, Oki T (1991) Synthesis, stereochemistry, and biological properties of the depigmenting agents, melanostatin, feldamycin and analogs. J Antibiot 44(1):76–85

    Article  PubMed  CAS  Google Scholar 

  • Ismail F, Levitsky D, Dembitsky V (2009) Aziridine alkaloids as potential therapeutic agents. Eur J Med Chem 44(9):3373–3387

    Article  PubMed  CAS  Google Scholar 

  • Ishida N, Kumagai K, Niida T, Hamamoto K, Shomura T (1967) Nojirimycin, a new antibiotic. I. Taxonomy and fermentation. J Antibiot 20(2):62–65

    PubMed  CAS  Google Scholar 

  • Ittah Y, Sasson Y, Shahak I, Tsaroom S, Blum J (1978) A new Aziridine synthesis from 2-azido alcohols and tertiary phosphines. Preparation of Phenanthrene 9, 10-imine. J Org Chem 43(22):4271–4273

    Article  Google Scholar 

  • Koehn F (2008) New strategies and methods in the discovery of natural product anti-infective agents: the mannopeptimycins. J Med Chem 51(9):2613–2617

    Article  PubMed  CAS  Google Scholar 

  • Kuo M, Yurek D, Mizsak S (1989) Structure elucidation of ficellomycin. J Antibiot 42(3):357–360

    Article  PubMed  CAS  Google Scholar 

  • Leclercq R, Courvalin P (1991) Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob Agents Chemother 35(7):1267–1272

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Liu C, Kelly GT, Watanabe CM (2006) In vitro biosynthesis of the antitumor agent azinomycin B. Org Lett 8(6):1065–1068

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Li M, Mu H, Song S, Zhang Y, Chen K, He X, Wang H, Dai Y, Lu F, Yan Z, Zhang H (2017) Identification and characterization of the ficellomycin biosynthesis gene cluster from Streptomyces ficellus. Appl Microbiol Biotechnol 101(20):7589–7602

    Article  PubMed  CAS  Google Scholar 

  • Matamoros S, Gras-Leguen C, Vacon F, Potel G, Cochetiere M (2013) Development of intestinal microbiota in infants and its impact on health. Trends Microbiol 21(4):167–173

    Article  PubMed  CAS  Google Scholar 

  • Maxson T, Mitchell D (2016) Targeted treatment for bacterial infections: prospects for pathogen-specific antibiotics coupled with rapid diagnostics. Tetrahedron 72(25):3609–3624

    Article  PubMed  CAS  Google Scholar 

  • McMechen M. (2016) Synthesis of the Azabicyclo[3.1.0]hexane Ring Core of Ficellomycin. Proceedings of the national conference on undergraduate research (NCUR). Doi: http://ncurproceedings.org/ojs/index.php/NCUR2016/article/view/1671

  • Moran G, Drishnadasan A, Gorwitz R, Fosheim G, McDougal L, Roberta B, Talan D (2006) Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 355:666–674

    Article  PubMed  CAS  Google Scholar 

  • Nepal KK, Lee RP, Rezenom YH, Watanabe CM (2015) Probing the role of N-acetyl-glutamyl 5-phosphate, an acyl phosphate, in the construction of the azabicycle moiety of the azinomycins. Biochemistry 54(29):4415–4418

    Article  PubMed  CAS  Google Scholar 

  • Ohnuki T, Imanaka T, Aiba S (1985) Isolation of streptomycin-nonproducing mutants deficient in biosynthesis of the streptidine moiety or linkage between streptidine 6-phosphate and dihydrostreptose. Antimicrob Agents Chemother 27(3):367–374

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Paumier D, Garcia M, Shipman M, Muir J (2004) Rapid assembly of the 1-Azabicyclo[3.1.0]hexane skeleton of ficellomycin. Synlett (12):2212–2214

  • Penesyan A, Gillings M, Paulsen I (2015) Antibiotic discovery: combatting bacterial resistance in cells and in biofilm communities. Molecules 20(4):5286–5298

    Article  PubMed  CAS  Google Scholar 

  • Pendleton A, Kocher M (2015) Methicillin-resistant staphylococcus aureus bone and joint infections in children. J Am Acad Orthop Surg 23(1):29–37

    Article  PubMed  Google Scholar 

  • Reusser F (1977) Ficellomycin and feldamycin; inhibitors of bacterial semiconservative DNA replication. Biochemistry 16(15):3406–3412

    Article  PubMed  CAS  Google Scholar 

  • Berlinck RG, Bertonha AF, Takaki M, Rodriguez JPG (2017) The chemistry and biology of guanidine natural products. Nat Prod Rep 34(11):1247–1334

    Article  Google Scholar 

  • Sears P, Ichikawa Y, Ruiz N, Gorbach S (2013) Advances in the treatment of Clostridium difficile with fidaxomicin: a narrow spectrum antibiotic. Ann N Y Acad Sci 1291:33–41

    Article  PubMed  CAS  Google Scholar 

  • Schito G (2006) The importance of the development of antibiotic resistance in Staphylococcus aureus. Clin Microbio Infect 12:3–8

    Article  CAS  Google Scholar 

  • Thibodeaux C, Chang W, Liu H (2012) Enzymatic chemistry of cyclopropane, epoxide, and aziridine biosynthesis. Chem Rev 112(3):1681–1709

    Article  PubMed  CAS  Google Scholar 

  • Walsh C, Wencewicz T (2014) Prospects for new antibiotics: a molecule-centered perspective. J Antibiot 67(1):7–22

    Article  PubMed  CAS  Google Scholar 

  • Wise E, Park J (1965) Penicillin: its basic site of action as an inhibitor of a peptide cross-linking reaction in the cell wall mucopeptide synthesis. Nat Acad of Sci 54:75–81

    Article  CAS  Google Scholar 

  • Zhao Q, He Q, Ding W, Tang M, Kang Q, Yu Y, Deng W, Zhang Q, Fang J, Tang G, Liu W (2008) Characterization of the azinomycin B biosynthetic gene cluster revealing a different iterative type I polyketide synthase for naphthoate biosynthesis. Chem Biol 15(7):693–705

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This research was financially supported by the National Natural Science Foundation of China (Grant No. 81373309) and the National High-Tech Research and Development Plan of China (Grant No. 2013AA102803; Task No. 2013AA102803C).

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Correspondence to Huitu Zhang.

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The authors declare that they have no conflict of interest.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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He, X., Li, M., Song, S. et al. Ficellomycin: an aziridine alkaloid antibiotic with potential therapeutic capacity. Appl Microbiol Biotechnol 102, 4345–4354 (2018). https://doi.org/10.1007/s00253-018-8934-4

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  • DOI: https://doi.org/10.1007/s00253-018-8934-4

Keywords

  • Ficellomycin
  • Antibiotics
  • Aziridine
  • Streptomyces ficellus
  • MRSA