Synthesis of Two Analogues of Xylapeptide A and Their Potency as New Antimicrobial Agent

Rani Maharani; Handi Nugraha Muchlis; Ace Tatang Hidayat; Jamaludin Al-Anshori; Nurlelasari Nurlelasari; Desi Harneti; Tri Mayanti; Kindi Farabi; Unang Supratman

doi:10.22146/ijc.100353

Synthesis of Two Analogues of Xylapeptide A and Their Potency as New Antimicrobial Agent

https://doi.org/10.22146/ijc.100353

Rani Maharani^(1*), Handi Nugraha Muchlis⁽²⁾, Ace Tatang Hidayat⁽³⁾, Jamaludin Al-Anshori⁽⁴⁾, Nurlelasari Nurlelasari⁽⁵⁾, Desi Harneti⁽⁶⁾, Tri Mayanti⁽⁷⁾, Kindi Farabi⁽⁸⁾, Unang Supratman⁽⁹⁾

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(2) PT. Kimia Farma Tbk. Plant Banjaran, Jl. Raya Banjaran, Km. 16, Bandung 40379, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(6) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(7) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(8) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(9) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Central Laboratory of Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia; Study Center of Exploration and Utilization of Natural Sources and Environment, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(*) Corresponding Author

Abstract

Xylapeptide A, derived from the fungus Xylaria sp. x Sophora tonkinensis, exhibits potent and selective antimicrobial properties. Our research group has successfully synthesized xylapeptide A. In our recent work, two xylapeptide A analogues (An1 and An2) were synthesized using a combination of solid- and solution-phase synthesis methods. The linear precursors of An1 and An2 were synthesized on 2-CTC resin with the Fmoc strategy. The coupling reagents HBTU/HOBt and HATU/HOAt were employed. Subsequently, the linear precursor was cleaved from the resin using either 20% TFA or a TFE mixture, and then cyclized in solution phase with HBTU. The synthesized products were purified using semi-preparative RP-HPLC, giving the percent yields 16% for An1 and 12% for An2. Both compounds were then characterized by HR-ToF-MS, ¹H- and ¹³C-NMR. The synthesized xylapeptide A and its analogues were evaluated against Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, and Candida albicans. The result showed that An2, possessing arginine residue, exhibited higher activity compared to xylapeptide A and An1. This research suggests that xylapeptide A analogues hold great promise as novel antimicrobial agents.

Keywords

antimicrobial peptides; cyclopentapeptides; xylapeptide A; solid-phase peptide synthesis; peptide cyclization

Full Text:

Full Text PDF Full Text PDF-Suppl. Data

References

[1] Xu, W.F., Hou, X.M., Yao, F.H., Zheng, N., Li, J., Wang, C.Y., Yang, R.Y., and Shao, C.L., 2017, Xylapeptide A, an antibacterial cyclopentapeptide with an uncommon L-pipecolinic acid moiety from the associated fungus Xylaria sp. (GDG-102), Sci. Rep., 7 (1), 6937.

[2] Räder, A.F., Reichart, F., Weinmüller, M., and Kessler, H., 2018, Improving oral bioavailability of cyclic peptides by N-methylation, Bioorg. Med. Chem., 26 (10), 2766−2773.

[3] Kurnia, D.Y., Maharani, R., Hidayat, A.T., Al‐Anshori, J., Wiani, I., Mayanti, T., Nurlelasari, N., Harneti, D., and Supratman, U., 2022, Total synthesis of xylapeptide B [Cyclo‐(L‐Leu‐L‐Pro‐N‐Me‐Phe‐L‐Val‐D‐Ala)], J. Heterocycl. Chem., 59 (1), 131−136.

[4] Muchlis, H.N., Kurnia, D.Y., Maharani, R., Zainuddin, A., Harneti, D., Nurlelasari, N., Mayanti, T., Farabi, K., Hidayat, A.T., and Supratman, U., 2023, Total synthesis and antimicrobial evaluation of xylapeptide A, J. Heterocycl. Chem., 60 (1), 39−46.

[5] Torres, M.D.T., Sothiselvam, S., Lu, T.K., and de la Fuente-Nunez, C., 2019, Peptide design principles for antimicrobial applications, J. Mol. Biol., 431 (18), 3547−3567.

[6] Maharani, R., Napitupulu, O.I., Dirgantara, J.M., Hidayat, A.T., Sumiarsa, D., Harneti, D., Nurlelasari, N., Supratman, U., and Fukase, K., 2021, Synthesis of cyclotetrapeptide analogues of c-PLAI and evaluation of their antimicrobial properties, R. Soc. Open Sci., 8 (3), 201822.

[7] Zhong, C., Zhu, N., Zhu, Y., Liu, T., Gou, S., Xie, J., Yao, J., and Ni, J., 2020, Antimicrobial peptides conjugated with fatty acids on the side chain of D-amino acid promises antimicrobial potency against multidrug-resistant bacteria, Eur. J. Pharm. Sci., 141, 105123.

[8] Dougherty, P.G., Sahni, A., and Pei, D., 2019, Understanding cell penetration of cyclic peptides, Chem. Rev., 119 (17), 10241−10287.

[9] Selvam, R., and Subashchandran, K.P., 2015, Synthesis of biologically active hydrophobic peptide by using novel polymer support: Improved Fmoc solid phase methodology, Int. J. Pept. Res. Ther., 21, 91−97.

[10] Siow, A., Opiyo, G., Kavianinia, I., Li, F.F., Furkert, D.P., Harris, P.W.R., and Brimble, M.A., 2018, Total synthesis of the highly N-methylated acetylene-containing anticancer peptide jahanyne, Org. Lett., 20 (3), 788−791.

[11] Davies, J.S., 2003, The cyclization of peptides and depsipeptides, J. Pept. Sci., 9 (8), 471−501.

[12] Hill, T.A., Shepherd, N.E., Diness, F., and Fairlie, D.P., 2014, Constraining cyclic peptides to mimic protein structure motifs, Angew. Chem. Int. Ed., 53 (48), 13020−13041.

[13] Prior, A.M., Hori, T., Fishman, A., and Sun, D., 2018, Recent reports of solid-phase cyclohexapeptide synthesis and applications, Molecules, 23 (6), 1475.

[14] Bechtler, C., and Lamers, C., 2021, Macrocyclization strategies for cyclic peptides and peptidomimetics, RSC Med. Chem., 12 (8), 1325−1351.

[15] Napitupulu, O.I., Sumiarsa, D., Subroto, T., Nurlelasari, N., Harneti, D., Supratman, U., and Maharani, R., 2019, Synthesis of cyclo-PLAI using a combination of solid-and solution-phase methods, Synth. Commun., 49 (2), 308−315.

[16] Muhajir, M.I., Hardianto, A., Al‐Anshori, J., Sumiarsa, D., Mayanti, T., Nurlelasari, N., Harneti, D., Hidayat, A.T., Supratman, U., and Maharani, R., 2021, Total synthesis of nocardiotide a by using a combination of solid‐ and solution‐phase methods, ChemistrySelect, 6 (45), 12941–12946.

[17] Chen, Y.X., Liu, C., Liu, N., Wu, Y., Zhao, Q.J., Hu, H.G., Li, X., and Zou, Y., 2018, Total synthesis and antibacterial study of cyclohexapeptides desotamide B, wollamide B and their analogs, Chem. Biodiversity, 15 (1), e1700414.

[18] Behrendt, R., White, P., and Offer, J., 2016, Advances in Fmoc solid‐phase peptide synthesis, J. Pept. Sci., 22 (1), 4−27.

[19] Hayes, H.C., Luk, L.Y.P., and Tsai, Y.H., 2021, Approaches for peptide and protein cyclisation, Org. Biomol. Chem., 19 (18), 3983−4001.

[20] Silva, F.F.A., Fernandes, C.C., Santiago, M.B., Martins, C.H.G., Vieira T.M., Crotti A.E.M., and Miranda, M.L.D., 2020, Chemical composition and in vitro antibacterial activity of essential oils from Murraya paniculata (L.) Jack (Rutaceae) ripe and unripe fruits against bacterial genera Mycobacterium and Streptococcus, Braz. J. Pharm. Sci., 56, e8371.

[21] Napolitano, A., Bruno, I., Riccio, R., and Gomez-Paloma, L., 2005, Synthesis, structure, and biological aspects of cyclopeptides related to marine phakellistatins 7–9, Tetrahedron, 61 (28), 6808−6815.

[22] Powers, J.P.S., and Hancock, R.E., 2003, The relationship between peptide structure and antibacterial activity, Peptides, 24 (11), 1681−1691.

[23] Zhang, R., Xu, L., and Dong, C., 2022, Antimicrobial peptides: An overview of their structure, function and mechanism of action, Protein Pept. Lett., 29 (8), 641−650.

[24] Jibroo, R.N., Mustafa, Y.F., and Al-Shakarchi, W., 2024, Synthesis and evaluation of linearly fused thiadiazolocoumarins as prospects with broad-spectrum bioactivity, Results Chem., 7, 101494.

[25] Zeki, N.M., and Mustafa, Y.F., 2024, Synthesis and evaluation of novel ring-conjugated coumarins as biosafe broad-spectrum antimicrobial candidates, J. Mol. Struct., 1309, 138192.

[26] Huan, Y., Kong, Q., Mou, H., and Yi, H., 2020, Antimicrobial peptides: Classification, design, application and research progress in multiple fields, Front. Microbiol., 11, 582779.

[27] Agrillo, B., Porritiello, A., Gratino, L., Balestrieri, M., Proroga, Y.T., Mancusi, A., Cozzi, L., Vicenza, T., Dardano, P., Miranda, B., Escribá, P.V., Gogliettino, M., and Palmieri, G., 2023, Antimicrobial activity, membrane interaction and structural features of short arginine-rich antimicrobial peptides, Front. Microbiol., 14, 1244325.

[28] Cutrona, K.J., Kaufman, B.A., Figueroa, D.M., and Elmore, D.E., 2015, Role of arginine and lysine in the antimicrobial mechanism of histone-derived antimicrobial peptides, FEBS Lett., 589 (24 Pt. B), 3915−3920.

[29] Zorila, B., Necula, G., Janosi, L., Turcu, I., Bacalum, M., and Radu, M., 2025, Interaction of arginine and tryptophan-rich short antimicrobial peptides with membrane models: A combined fluorescence, simulations, and theoretical approach, J. Chem. Inf. Model., 65 (7), 3723–3736.

DOI: https://doi.org/10.22146/ijc.100353