Abstract
A series of compounds based on the structure of bacilysin were synthesised and tested for antibacterial activity. The key steps in the syntheses are the coupling of an iodide to a diketopiperazine (DKP) and mono-lactim ether scaffold, respectively. The diastereoselectivity of the coupling reactions was dependant on the scaffold, with selectivity for DKP of about 4:1 and mono-lactim ether exceeding 98:2. Subsequent elaboration of the compounds to give open chain dipeptides and DKPs that mimic the structure of bacilysin but substitute the epoxy ketone for a saturated or unsaturated ketone is described. Overall yield from coupling to final product was between 5 and 21 %, with the yield of the saturated products notably higher. The open chain dipeptides demonstrated moderate antibacterial and antifungal activity.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Baldwin JE, Adlington RM, Mitchell MB (1995) Stereocontrolled enantiospecific synthesis of anticapsin. Tetrahedron 51:5193–5206
Bates CJ, Adams WR, Handschumacher RE (1966) Control of formation of uridine diphospho-n-acetyl-hexosamine and glycoprotein synthesis in rat liver. J Biol Chem 241:1705–1712
Bearne SL, Blouin C (2000) Inhibition of Escherichia coli glucosamine-6 phosphate synthase by reactive intermediate analogues—the role of the 2-amino function in catalysis. J Biol Chem 275:135–140
Chmara H (1985) Inhibition of glucosamine synthase by bacilysin and anticapsin. J Gen Microbiol 131:265–271
Chmara H, Milewski S, Dzieduszycka M, Smulkowski M, Sawlewicz P, Borowski E (1982) Epoxypeptides—a novel group of metabolic-inhibitors in prokaryotic and eukaryotic microorganisms. Drugs Exp Clin Res 8:11–20
Chmara H, Zahner H, Borowski E (1984) Anticapsin, an active-site directed irreversible inhibitor of glucosamine-6-phosphate synthetase from Escherichia coli. J Antibiot 37:1038–1043
Davies J, Davies D (2010) Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev 74:417–433
Davies SG, Garner AC, Ouzman JVA, Roberts PM, Smith AD, Snow EJ, Thomson JE, Tamayo JA, Vickers RJ (2007) Diastereoselective synthesis of quaternary alpha-amino acids from diketopiperazine templates. Org Biomol Chem 5:2138–2147
Foster JW, Woodruff HB (1946) Bacillin, a new antibiotic substance from a soil isolate of Bacillus subtilis. J Bacteriol 51:363–369
Gonzalez-Ibarra J, Milewski S, Villagomez-Castor JC, Cano-Canchola C, Lopez-Romero E (2010) Sporothrix schenckii: purification and partial biochemical characterization of glucosamine-6-phosphate synthase, a potential antifungal target. Med Mycol 48:110–121
Jedrzejczak R, Wojciechowski M, Andruszkiewicz R, Sowinski P, Kot-Wasik A, Milewski S (2012) Inactivation of glucosamine-6-phosphate synthase by N3-oxoacyl derivatives of L-2,3-diaminopropanoic acid. ChemBioChem 13:85–96
Kenig M, Abraham EP (1976) Antimicrobial activities and antagonists of bacilysin and anticapsin. J Gen Microbiol 94:37–45
Kenig M, Vandamme E, Abraham EP (1976) Mode of action of bacilysin and anticapsin and biochemical properties of bacilysin-resistant mutants. J Gen Microbiol 94:46–54
Lestini E, Robertson K, Murphy CD, Paradisi F (2012) Alternative mild route to the synthesis of 4-methylenecyclohex-2-enone, a key moiety of the anticancer compounds ottelione A and B. Synth Commun 42(12):1864–1876
Mathers CD, Boerma T, Fat DM (2009) Global and regional causes of death. Br Med Bull 92(1):7–32
Nicolaou KC, Montagnon T, Baran PS (2002) HIO3 and I2O5: mild and selective alternative reagents to IBX for the dehydrogenation of aldehydes and ketones. Angewandte Chemie-Int Edition 41(8):1386–1389
O’Reilly E, Lestini E, Baiducci D, Paradisi F (2009) One-step diketopiperazine synthesis using phase transfer catalysis. Tetrahedron Lett 50(15):1748–1750
Paradisi F, Porzi G, Sandri S (2001) A new stereocontrolled synthesis of uncommon tripeptides derived from 2,6-diaminopimelic acid (2,6-DAP). Tetrahedron Asymmetry 12(23):3319–3324. doi:10.1016/s0957-4166(02)00002-2
Perry D, Abraham EP (1979) Transport and metabolism of bacilysin and other peptides by suspensions of Staphylococcus aureus. J Gen Microbiol 115:213–221
So AD, Gupta N, Brahmachari SK, Chopra I, Munos B, Nathan C, Outterson K, Paccaud JP, Payne DJ, Peeling RW, Spigelman M, Weigelt J (2011) Towards new business models for R&D for novel antibiotics. Drug Resist Updates 14:88–94
Spellberg B, Powers JH, Brass EP, Miller LG, Edwards JE (2004) Trends in antimicrobial drug development: implications for the future. Clin Infect Dis 38(9):1279–1286
Wild H (1994) Enantioselective total synthesis of the antifungal natural-products chlorotetaine, bacilysin, and anticapsin and of related-compounds—revision of the relative configuration. J Org Chem 59(10):2748–2761
Wipf P, Jeger P, Kim Y (1998) Thiophilic ring-opening and rearrangement reactions of epoxyketone natural products. Bioorg Med Chem Lett 8(4):351–356
Wojciechowski M, Milewski S, Mazerski J, Borowski E (2005) Glucosamine-6-phosphate synthase, a novel target for antifungal agents. Molecular modelling studies in drug design. Acta Biochim Pol 52(3):647–653
Acknowledgments
This projected was funded under the Irish Government’s Programme for Research Training in Third Level Institutes (PRTLI). The authors thank Dr Maria Martins of the UCD Centre for Food Safety for conducting the microtitre plate assays.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Robertson, K., Murphy, C.D. & Paradisi, F. The synthesis and biological testing of bacilysin analogues. Amino Acids 45, 1157–1168 (2013). https://doi.org/10.1007/s00726-013-1571-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-013-1571-4