Rational search for natural antimicrobial compounds: relevance of sesquiterpene lactones

doi:10.1007/s13659-025-00513-y

应用天然产物 ›› 2025, Vol. 15 ›› Issue (3): 28-28.DOI: 10.1007/s13659-025-00513-y

Rational search for natural antimicrobial compounds: relevance of sesquiterpene lactones

Alejandro Recio-Balsells^1,2, Eugenia Rodriguez Ristau^1,2, Adriana Pacciaroni^1,2, Viviana Nicotra^1,2, Carina Casero^1,2, Manuela García^1,2

1. Instituto Multidisciplinario de Biología Vegetal (IMBIV), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina;
2. Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Ciudad Universitaria, X5000HUA, Córdoba, Argentina

收稿日期:2025-02-17 接受日期:2025-04-15 出版日期:2025-06-24 发布日期:2025-06-18
通讯作者: Manuela García Email:E-mail:manuelagarcia@unc.edu.ar
基金资助:
This work has been financed by ONR Global [Grant N62909-21-1-2052, USA], CONICET [grant number PIP-CONICET 2022-2024, 11220200101065CO], ANPCyT [grant numbers PICT 2020- SERIEA-02162 (2022-2025) and PICT 2020- SERIEA-3702 (2022-2024)], and SeCyT-UNC [grant number 2023-CONSOLIDAR-33620230100785CB01].

Rational search for natural antimicrobial compounds: relevance of sesquiterpene lactones

Alejandro Recio-Balsells^1,2, Eugenia Rodriguez Ristau^1,2, Adriana Pacciaroni^1,2, Viviana Nicotra^1,2, Carina Casero^1,2, Manuela García^1,2

1. Instituto Multidisciplinario de Biología Vegetal (IMBIV), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina;
2. Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), Ciudad Universitaria, X5000HUA, Córdoba, Argentina

Received:2025-02-17 Accepted:2025-04-15 Online:2025-06-24 Published:2025-06-18
Supported by:
This work has been financed by ONR Global [Grant N62909-21-1-2052, USA], CONICET [grant number PIP-CONICET 2022-2024, 11220200101065CO], ANPCyT [grant numbers PICT 2020- SERIEA-02162 (2022-2025) and PICT 2020- SERIEA-3702 (2022-2024)], and SeCyT-UNC [grant number 2023-CONSOLIDAR-33620230100785CB01].

摘要/Abstract

摘要： Antimicrobial resistance is one of the most pressing global health challenges, as many pathogens are rapidly evolving to evade existing treatments. Despite this urgent need for new solutions, natural plant-derived compounds remain relatively underexplored in the development of antimicrobial drugs. This report highlights an innovative approach to discovering potent antimicrobial agents through bioguided fractionation of numerous plant species from the rich Argentinean flora. By systematically screening 60 species (over 177 extracts) for antimicrobial activity against representative strains of gram-positive and gram-negative bacteria, we identified promising bioactive compounds within the Asteraceae family—particularly sesquiterpene lactones from the Xanthium genus. Building on this basis, we synthesized semi-synthetic derivatives by chemically modifying plant sub-extracts, focusing on structures incorporating heteroatoms and/or heterocycles containing oxygen and nitrogen (important for the bioavailability and bioactivity that they are capable of providing). These modifications were evaluated for their potential to enhance antimicrobial efficacy against bacteria and Candida species, including resistant strains. Our findings suggest that tailoring natural metabolites from Xanthium and related Asteraceae species can significantly improve their antimicrobial properties. This strategy offers a promising pathway for the development of novel therapeutic agents to combat bacterial and fungal infections in an era of rising drug resistance.

关键词: Sesquiterpene lactones, Antimicrobials, Semisynthetic derivatives, Bioguided study, Extract derivatization

Abstract: Antimicrobial resistance is one of the most pressing global health challenges, as many pathogens are rapidly evolving to evade existing treatments. Despite this urgent need for new solutions, natural plant-derived compounds remain relatively underexplored in the development of antimicrobial drugs. This report highlights an innovative approach to discovering potent antimicrobial agents through bioguided fractionation of numerous plant species from the rich Argentinean flora. By systematically screening 60 species (over 177 extracts) for antimicrobial activity against representative strains of gram-positive and gram-negative bacteria, we identified promising bioactive compounds within the Asteraceae family—particularly sesquiterpene lactones from the Xanthium genus. Building on this basis, we synthesized semi-synthetic derivatives by chemically modifying plant sub-extracts, focusing on structures incorporating heteroatoms and/or heterocycles containing oxygen and nitrogen (important for the bioavailability and bioactivity that they are capable of providing). These modifications were evaluated for their potential to enhance antimicrobial efficacy against bacteria and Candida species, including resistant strains. Our findings suggest that tailoring natural metabolites from Xanthium and related Asteraceae species can significantly improve their antimicrobial properties. This strategy offers a promising pathway for the development of novel therapeutic agents to combat bacterial and fungal infections in an era of rising drug resistance.

Key words: Sesquiterpene lactones, Antimicrobials, Semisynthetic derivatives, Bioguided study, Extract derivatization

Alejandro Recio-Balsells, Eugenia Rodriguez Ristau, Adriana Pacciaroni, Viviana Nicotra, Carina Casero, Manuela García. Rational search for natural antimicrobial compounds: relevance of sesquiterpene lactones[J]. 应用天然产物, 2025, 15(3): 28-28.

参考文献

1. Global antimicrobial resistance and use surveillance system (GLASS) report 2022. Geneva: World Health Organization; 2022. Licence: CC BY-NC-SA 3.0 IGO.
2. Lancet T. Antimicrobial resistance: an agenda for all. The Lancet. 2024;403:2349. https://doi.org/10.1016/S0140-6736(24)01076-6.
3. O’Neill J. Antimicrobial Resistance: Tackling a crisis for the health and wealth of nations, The Review on Antimicrobial Resistance (2014) 1-17.
4. Chinemerem Nwobodo D, Ugwu MC, Oliseloke Anie C, Al-Ouqaili MTS, Chinedu Ikem J, Victor Chigozie U, Saki M. Antibiotic resistance: the challenges and some emerging strategies for tackling a global menace. J Clin Lab Anal. 2022;36:e24655-e24655. https://doi.org/10.1002/jcla.24655.
5. Rice LB. Progress and challenges in implementing the research on ESKAPE pathogens. Infect Control Hosp Epidemiol. 2010;31:S7-10. https://doi.org/10.1086/655995.
6. Robbins N, Caplan T, Cowen LE. Molecular evolution of antifungal drug resistance. Annu Rev Microbiol. 2017;71:753-75. https://doi.org/10.1146/annurev-micro-030117-020345.
7. Bhattacharya S, Sae-Tia S, Fries BC. Candidiasis and mechanisms of antifungal resistance. Antibiotics. 2020. https://doi.org/10.3390/antibiotics9060312.
8. Fisher MC, Alastruey-Izquierdo A, Berman J, Bicanic T, Bignell EM, Bowyer P, Bromley M, Brüggemann R, Garber G, Cornely OA, Gurr SJ, Harrison TS, Kuijper E, Rhodes J, Sheppard DC, Warris A, White PL, Xu J, Zwaan B, Verweij PE. Tackling the emerging threat of antifungal resistance to human health. Nat Rev Microbiol. 2022;20:557-71. https://doi.org/10.1038/s41579-022-00720-1.
9. Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod. 2020;83:770-803. https://doi.org/10.1021/acs.jnatprod.9b01285.
10. Wright GD. Opportunities for natural products in 21st century antibiotic discovery. Nat Prod Rep. 2017;34:694-701. https://doi.org/10.1039/C7NP00019G.
11. Stratton CF, Newman DJ, Tan DS. Cheminformatic comparison of approved drugs from natural product versus synthetic origins. Bioorg Med Chem Lett. 2015;25:4802-7. https://doi.org/10.1016/j.bmcl.2015.07.014.
12. Porras G, Chassagne F, Lyles JT, Marquez L, Dettweiler M, Salam AM, Samarakoon T, Shabih S, Farrokhi DR, Quave CL. Ethnobotany and the role of plant natural products in antibiotic drug discovery. Chem Rev. 2021;121:3495-560. https://doi.org/10.1021/acs.chemrev.0c00922.
13. Álvarez-Martínez FJ, Barrajón-Catalán E, Herranz-López M, Micol V. Antibacterial plant compounds, extracts and essential oils: an updated review on their effects and putative mechanisms of action. Phytomedicine. 2021;90:153626. https://doi.org/10.1016/j.phymed.2021.153626.
14. Zhang C-W, Zhong X-J, Zhao Y-S, Rajoka MSR, Hashmi MH, Zhai P, Song X. Antifungal natural products and their derivatives: a review of their activity and mechanism of actions. Pharmacol Res Modern Chin Med. 2023;7:100262. https://doi.org/10.1016/j.prmcm.2023.100262.
15. Aldholmi M, Marchand P, Ourliac-Garnier I, Le Pape P, Ganesan A. A decade of antifungal leads from natural products: 2010-2019. Pharmaceuticals. 2019. https://doi.org/10.3390/ph12040182.
16. Moujir L, Callies O, Sousa PMC, Sharopov F, Seca AML. Applications of sesquiterpene lactones: a review of some potential success cases. Appl Sci (Switzerland). 2020. https://doi.org/10.3390/app10093001.
17. Ayelen Ramallo I, Salazar MO, García P, Furlan RLE. Chapter 10—chemical diversification of natural product extracts. In: Atta-ur-Rahman, editor. Studies in Natural Products Chemistry. Elsevier; 2019. p. 371-98. https://doi.org/10.1016/B978-0-444-64181-6.00010-3.
18. Richter MF, Hergenrother PJ. The challenge of converting Gram-positive-only compounds into broad-spectrum antibiotics. Ann N Y Acad Sci. 2019;1435:18-38. https://doi.org/10.1111/nyas.13598.
19. Geddes EJ, Li Z, Hergenrother PJ. An LC-MS/MS assay and complementary web-based tool to quantify and predict compound accumulation in E. coli. Nat Protoc. 2021;16:4833-54. https://doi.org/10.1038/s41596-021-00598-y.
20. Onyedibe KI, Nemeth AM, Dayal N, Smith RD, Lamptey J, Ernst RK, Melander RJ, Melander C, Sintim HO. Re-sensitization of multidrug-resistant and colistin-resistant gram-negative bacteria to colistin by povarov/doebner-derived compounds. ACS Infect Dis. 2023;9:283-95. https://doi.org/10.1021/acsinfecdis.2c00417.
21. Caesar LK, Cech NB. Synergy and antagonism in natural product extracts: when 1 + 1 does not equal 2. Nat Prod Rep. 2019;36:869-88. https://doi.org/10.1039/C9NP00011A.
22. Eloff JN. Avoiding pitfalls in determining antimicrobial activity of plant extracts and publishing the results. BMC Complement Altern Med. 2019;19:106. https://doi.org/10.1186/s12906-019-2519-3.
23. González U, Morales-Jiménez J, Nieto-Camacho A, Martínez M, Maldonado E. Elemenolides from Zinnia peruviana and evaluation of their antibacterial and α-glucosidase inhibitory activities. Nat Prod Res. 2021;35:1977-84. https://doi.org/10.1080/14786419.2019.1648461.
24. Julianti E, Jang KH, Lee S, Lee D, Mar W, Oh K-B, Shin J. Sesquiterpenes from the leaves of Laurus nobilis L. Phytochemistry. 2012;80:70-6. https://doi.org/10.1016/j.phytochem.2012.05.013.
25. Jamuna S, Karthika K, Paulsamy S, Thenmozhi K, Kathiravan S, Venkatesh R. Confertin and scopoletin from leaf and root extracts of Hypochaeris radicata have anti-inflammatory and antioxidant activities. Ind Crops Prod. 2015;70:221-30. https://doi.org/10.1016/j.indcrop.2015.03.039.
26. Olivaro C, Rostan V, Bandera D, Moyna G, Vazquez A. Xanthane sesquiterpenoids from the roots and flowers of Xanthium cavanillesii. Nat Prod Res. 2016;30:2238-42. https://doi.org/10.1080/14786419.2016.1149709.
27. Yuan Z, Zheng X, Zhao Y, Liu Y, Zhou S, Wei C, Hu Y, Shao H. Phytotoxic compounds isolated from leaves of the invasive weed Xanthium spinosum. Molecules. 2018. https://doi.org/10.3390/molecules23112840.
28. Kummer DA, Brenneman JB, Martin SF. Application of a domino intramolecular enyne metathesis/cross metathesis reaction to the total synthesis of (+)-8-epi-xanthatin. Org Lett. 2005;7:4621-3. https://doi.org/10.1021/ol051711a.
29. Marco JA, Sanz-Cervera JF, Corral J, Carda M, Jakupovic J. Xanthanolides from Xanthium: absolute configuration of xanthanol, isoxanthanol and their C-4 epimers. Phytochemistry. 1993;34:1569-76. https://doi.org/10.1016/S0031-9422(00)90847-1.
30. Yang L, Wen K-S, Ruan X, Zhao Y-X, Wei F, Wang Q. Response of plant secondary metabolites to environmental factors. Molecules. 2018. https://doi.org/10.3390/molecules23040762.
31. Verma N, Shukla S. Impact of various factors responsible for fluctuation in plant secondary metabolites. J Appl Res Med Aromat Plants. 2015;2:105-13. https://doi.org/10.1016/j.jarmap.2015.09.002.
32. Pavarini DP, Pavarini SP, Niehues M, Lopes NP. Exogenous influences on plant secondary metabolite levels. Anim Feed Sci Technol. 2012;176:5-16. https://doi.org/10.1016/j.anifeedsci.2012.07.002.
33. Tsankova ET, Trendafilova AB, Kujumgiev AI, Galabov AS, Robeva PR. Xanthanolides of Xanthium italicum Moretti and their biological activity. Zeitschrift für Naturforschung C. 1994;49:154-6. https://doi.org/10.1515/znc-1994-1-223.
34. Sato Y, Oketani H, Yamada T, Singyouchi K-I, Ohtsubo T, Kihara M, Shibata H, Higuti T. a Xanthanolide with potent antibacterial activity against methicillin-resistant Staphylococcus aureus. J Pharmacy Pharmacol. 1997;49:1042-4. https://doi.org/10.1111/j.2042-7158.1997.tb06038.x.
35. Lavault M, Landreau A, Larcher G, Bouchara J-P, Pagniez F, Le Pape P, Richomme P. Antileishmanial and antifungal activities of xanthanolides isolated from Xanthium macrocarpum. Fitoterapia. 2005;76:363-6. https://doi.org/10.1016/j.fitote.2005.03.019.
36. Yang C, Li Y, Zhang Y, Hu Q, Liu Y, Li Y, Shi H, Song L, Cao H, Hao X, Zhi X. Natural Sesquiterpene lactone as source of discovery of novel fungicidal candidates: structural modification and antifungal activity evaluation of xanthatin derived from Xanthium strumarium L. J Agric Food Chem. 2023;71:11239-51. https://doi.org/10.1021/acs.jafc.3c02435.
37. Zhi X, Song L, Liang J, Wei S, Li Y, Zhang Y, Hao X, Cao H, Yang C. Synthesis and in vitro antifungal activity of new Michael-type amino derivatives of xanthatin, a natural sesquiterpene lactone from Xanthium strumarium L. Bioorg Med Chem Lett. 2022;55:128481. https://doi.org/10.1016/j.bmcl.2021.128481.
38. Carlucci R, Lisa M-N, Labadie GR. 1,2,3-Triazoles in biomolecular crystallography: a geometrical data-mining approach. J Med Chem. 2023;66:14377-90. https://doi.org/10.1021/acs.jmedchem.3c01097.
39. Castro SJ, Padrón JM, Darses B, Nicotra VE, Dauban P. Late-stage Rh(II)-catalyzed nitrene transfer for the synthesis of guaianolide analogs with enhanced antiproliferative activity. Eur J Org Chem. 2021;2021:1859-63. https://doi.org/10.1002/ejoc.202100074.
40. Ayaz M, Ullah F, Sadiq A, Ullah F, Ovais M, Ahmed J, Devkota HP. Synergistic interactions of phytochemicals with antimicrobial agents: potential strategy to counteract drug resistance. Chem Biol Interact. 2019;308:294-303. https://doi.org/10.1016/j.cbi.2019.05.050.
41. Ma C-M, Abe T, Komiyama T, Wang W, Hattori M, Daneshtalab M. Synthesis, anti-fungal and 1,3-β-d-glucan synthase inhibitory activities of caffeic and quinic acid derivatives. Bioorg Med Chem. 2010;18:7009-14. https://doi.org/10.1016/j.bmc.2010.08.022.
42. Clinical and Laboratory Standards Institute (CLSI), 2006. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard—Seventh Edition. Clinical and Laboratory Standards Institute document M7-A7 [ISBN 1-56238-587-9]. Vol. 29, Clinical and Laboratory Standards Institute, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898 USA., (n.d.).
43. Coutinho HDM, Costa JGM, Falcão-Silva VS, Siqueira-Júnior JP, Lima EO. Potentiation of antibiotic activity by Eugenia uniflora and Eugenia jambolanum. J Med Food. 2010;13:1024-6. https://doi.org/10.1089/jmf.2009.0158.

Rational search for natural antimicrobial compounds: relevance of sesquiterpene lactones

Rational search for natural antimicrobial compounds: relevance of sesquiterpene lactones

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 0

编辑推荐

Metrics

本文评价