Promising Ursolic Acid as a Novel Antituberculosis Agent: Current Progress and Challenges

References

• Global tuberculosis report; 2022. Available from: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2022. Accessed September 2, 2023.
   Google Scholar
• Chinthanom P, Vichai V, Dokladda K, Sappan M, Thongpanchang C, Isaka M. Semisynthetic modifications of antitubercular lanostane triterpenoids from Ganoderma. J Antibiot. 2021;74(7):435–442. doi:10.1038/s41429-021-00422-5
   PubMed Web of Science ®Google Scholar
• Ku CM, Lin JY. Anti-inflammatory effects of 27 selected terpenoid compounds tested through modulating Th1/Th2 cytokine secretion profiles using murine primary splenocytes. Food Chem. 2013;141(2):1104–1113. doi:10.1016/j.foodchem.2013.04.044
   PubMed Web of Science ®Google Scholar
• Shanmugam MK, Dai X, Kumar AP, Tan BKH, Sethi G, Bishayee A. Ursolic acid in cancer prevention and treatment: molecular targets, pharmacokinetics and clinical studies. Biochem Pharmacol. 2013;85(11):1579–1587. doi:10.1016/j.bcp.2013.03.006
   PubMed Web of Science ®Google Scholar
• Liobikas J, Majiene D, Trumbeckaite S, et al. Uncoupling and antioxidant effects of ursolic acid in isolated rat heart mitochondria. J Nat Prod. 2011;74(7):1640–1644. doi:10.1021/np200060p
   PubMed Web of Science ®Google Scholar
• D’Abrosca B, Fiorentino A, Monaco P, Pacifico S. Radical-scavenging activities of new hydroxylated ursane triterpenes from cv. Annurca apples. Chem Biodivers. 2005;2(7):953–958. doi:10.1002/cbdv.200590072
   PubMed Web of Science ®Google Scholar
• Ali MS, Ibrahim SA, Jalil S, Choudhary MI. Ursolic acid: a potent inhibitor of superoxides produced in the cellular system. Phytother Res PTR. 2007;21(6):558–561. doi:10.1002/ptr.2108
   PubMed Web of Science ®Google Scholar
• Mallavadhani UV, Mahapatra A, Jamil K, Reddy PS. Antimicrobial activity of some pentacyclic triterpenes and their synthesized 3-O-lipophilic chains. Biol Pharm Bull. 2004;27(10):1576–1579. doi:10.1248/bpb.27.1576
   PubMed Web of Science ®Google Scholar
• e Silva M de L, David JP, Silva LCRC, et al. Bioactive oleanane, lupane and ursane triterpene acid derivatives. Mol. 2012;17(10):12197–12205. doi:10.3390/molecules171012197
   PubMed Web of Science ®Google Scholar
• Kurek A, Nadkowska P, Pliszka S, Wolska KI. Modulation of antibiotic resistance in bacterial pathogens by oleanolic acid and ursolic acid. Phytomedicine Int J Phytother Phytopharm. 2012;19(6):515–519. doi:10.1016/j.phymed.2011.12.009
   PubMed Web of Science ®Google Scholar
• Martins D, Carrion LL, Ramos DF, et al. Triterpenes and the antimycobacterial activity of duroia macrophylla Huber (Rubiaceae). BioMed Res Int. 2013;2013:e605831. doi:10.1155/2013/605831
   PubMed Web of Science ®Google Scholar
• Jyoti M, Zerin T, Kim TH, et al. In vitro effect of ursolic acid on the inhibition of Mycobacterium tuberculosis and its cell wall mycolic acid. Pulm Pharmacol Ther. 2015;33:17–24. doi:10.1016/j.pupt.2015.05.005
   PubMed Web of Science ®Google Scholar
• Pitaloka DAE, Sukandar EY. In vitro study of ursolic acid combination first-line antituberculosis drugs against drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. Asian J Pharm Clin Res. 2017;216–218. doi:10.22159/ajpcr.2017.v10i4.16582
   Google Scholar
• Jiménez-Arellanes A, Luna-Herrera J, Cornejo-Garrido J, et al. Ursolic and oleanolic acids as antimicrobial and immunomodulatory compounds for tuberculosis treatment. BMC Complement Altern Med. 2013;13:258. doi:10.1186/1472-6882-13-258
   PubMed Web of Science ®Google Scholar
• Kashyap D, Tuli HS, Sharma AK. Ursolic acid (UA): a metabolite with promising therapeutic potential. Life Sci. 2016;146:201–213. doi:10.1016/j.lfs.2016.01.017
   PubMed Web of Science ®Google Scholar
• PubChem. Ursolic Acid. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/64945. Accessed September 4, 2023.
   Google Scholar
• Nguyen HN, Ullevig SL, Short JD, Wang L, Ahn YJ, Asmis R. Ursolic acid and related analogues: triterpenoids with broad health benefits. Antioxidants. 2021;10(8):1161. doi:10.3390/antiox10081161
   Web of Science ®Google Scholar
• da Rosa RL, Nesello LÂN, Mariano LNB, et al. Gastroprotective activity of the methanol extract from peels of Plinia edulis (Vell.) Sobral fruits and its isolated triterpenes: maslinic and ursolic acids. Naunyn Schmiedebergs Arch Pharmacol. 2018;391(1):95–101. doi:10.1007/s00210-017-1442-8
   PubMed Web of Science ®Google Scholar
• Lv Y, Tahir II, Olsson ME. Factors affecting the content of the ursolic and oleanolic acid in apple peel: influence of cultivars, sun exposure, storage conditions, bruising and Penicillium expansum infection. J Sci Food Agric. 2016;96(6):2161–2169. doi:10.1002/jsfa.7332
   PubMed Web of Science ®Google Scholar
• Szakiel A, Pączkowski C, Pensec F, Bertsch C. Fruit cuticular waxes as a source of biologically active triterpenoids. Phytochem Rev Proc Phytochem Soc Eur. 2012;11(2–3):263–284. doi:10.1007/s11101-012-9241-9
   PubMed Web of Science ®Google Scholar
• Oleanolic acid and ursolic acid in commercial dried fruits. Available from: https://www.jstage.jst.go.jp/article/fstr/19/1/19_113/_article. Accessed September 21, 2023.
   Google Scholar
• Kalogeropoulos N, Yanni AE, Koutrotsios G, Aloupi M. Bioactive microconstituents and antioxidant properties of wild edible mushrooms from the island of Lesvos, Greece. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc. 2013;55:378–385. doi:10.1016/j.fct.2013.01.010
   PubMed Web of Science ®Google Scholar
• Qiang Z, Ye Z, Hauck C, et al. Permeability of rosmarinic acid in Prunella vulgaris and ursolic acid in Salvia officinalis extracts across Caco-2 cell monolayers. J Ethnopharmacol. 2011;137(3):1107–1112. doi:10.1016/j.jep.2011.07.037
   PubMed Web of Science ®Google Scholar
• Chen Q, Luo S, Zhang Y, Chen Z. Development of a liquid chromatography-mass spectrometry method for the determination of ursolic acid in rat plasma and tissue: application to the pharmacokinetic and tissue distribution study. Anal Bioanal Chem. 2011;399(8):2877–2884. doi:10.1007/s00216-011-4651-x
   PubMed Web of Science ®Google Scholar
• Liao Q, Yang W, Jia Y, Chen X, Gao Q, Bi K. LC-MS determination and pharmacokinetic studies of ursolic acid in rat plasma after administration of the traditional Chinese medicinal preparation Lu-Ying extract. Yakugaku Zasshi. 2005;125(6):509–515. doi:10.1248/yakushi.125.509
   PubMed Web of Science ®Google Scholar
• López-Hortas L, Pérez-Larrán P, González-Muñoz MJ, Falqué E, Domínguez H. Recent developments on the extraction and application of ursolic acid. A review. Food Res Int. 2018;103:130–149. doi:10.1016/j.foodres.2017.10.028
   PubMed Web of Science ®Google Scholar
• Xia E-Q, Yu -Y-Y, Xu X-R, Deng G-F, Guo Y-J, Li H-B. Ultrasound-assisted extraction of oleanolic acid and ursolic acid from Ligustrum lucidum Ait. Ultrason Sonochem. 2012;19(4):772–776. doi:10.1016/j.ultsonch.2011.11.014
   PubMed Web of Science ®Google Scholar
• Wójciak-Kosior M, Sowa I, Kocjan R, Nowak R. Effect of different extraction techniques on quantification of oleanolic and ursolic acid in Lamii albi flos. Ind Crops Prod. 2013;44:373–377. doi:10.1016/j.indcrop.2012.11.018
   Web of Science ®Google Scholar
• Idris FN, Nadzir MM. Comparative studies on different extraction methods of Centella asiatica and extracts bioactive compounds effects on antimicrobial activities. Antibiotics. 2021;10(4):457. doi:10.3390/antibiotics10040457
   Google Scholar
• Jin K, Shi X, Liu J, et al. Combinatorial metabolic engineering enables the efficient production of ursolic acid and oleanolic acid in Saccharomyces cerevisiae. Bioresour Technol. 2023;374:128819. doi:10.1016/j.biortech.2023.128819
   PubMed Web of Science ®Google Scholar
• Liu X, Ding W, Jiang H. Engineering microbial cell factories for the production of plant natural products: from design principles to industrial-scale production. Microb Cell Fact. 2017;16(1):125. doi:10.1186/s12934-017-0732-7
   PubMedGoogle Scholar
• Arnesen JA, Belmonte Del Ama A, Jayachandran S, et al. Engineering of Yarrowia lipolytica for the production of plant triterpenoids: asiatic, madecassic, and arjunolic acids. Metab Eng Commun. 2022:14:e00197. doi:10.1016/j.mec.2022.e00197
   PubMedGoogle Scholar
• Wang S, Zhao F, Yang M, Lin Y, Han S. Metabolic engineering of Saccharomyces cerevisiae for the synthesis of valuable chemicals. Crit Rev Biotechnol. 2023;1–28. doi:10.1080/07388551.2022.2153008
   Web of Science ®Google Scholar
• Huang L, Li J, Ye H, et al. Molecular characterization of the pentacyclic triterpenoid biosynthetic pathway in Catharanthus roseus. Planta. 2012;236(5):1571–1581. doi:10.1007/s00425-012-1712-0
   PubMed Web of Science ®Google Scholar
• Lu C, Zhang C, Zhao F, Li D, Lu W. Biosynthesis of ursolic acid and oleanolic acid in Saccharomyces cerevisiae. AiChE J. 2018;64(11):3794–3802. doi:10.1002/aic.16370
   Web of Science ®Google Scholar
• Unissa AN, Subbian S, Hanna LE, Selvakumar N. Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis. 2016;45:474–492. doi:10.1016/j.meegid.2016.09.004
   PubMed Web of Science ®Google Scholar
• Pitaloka DAE, Damayanti S, Artarini AA, Sukandar EY. Molecular Docking, Dynamics Simulation, and Scanning Electron Microscopy (SEM) Examination of Clinically Isolated Mycobacterium tuberculosis by Ursolic Acid: a Pentacyclic Triterpenes. Indones J Chem. 2019;19(2):328–336. doi:10.22146/ijc.33731
   Web of Science ®Google Scholar
• Ramon-Luing LA, Palacios Y, Ruiz A, Tellez-Navarrete NA, Chavez-Galan L. Virulence factors of mycobacterium tuberculosis as modulators of cell death mechanisms. Pathogens. 2023;12(6):839. doi:10.3390/pathogens12060839
   PubMed Web of Science ®Google Scholar
• Sundararajan S, Muniyan R. Latent tuberculosis: interaction of virulence factors in Mycobacterium tuberculosis. Mol Biol Rep. 2021;48(8):6181–6196. doi:10.1007/s11033-021-06611-7
   PubMed Web of Science ®Google Scholar
• Jacobo-Delgado YM, Navarro-Tovar G, Rivas-Santiago B. Potential use of liposomes in tuberculosis treatment. Rev Medica Inst Mex Seguro Soc. 2023;61(5):661–669. doi:10.5281/zenodo.8316467
   PubMedGoogle Scholar
• Schaefer CM, Lu R, Nesbitt NM, Schiebel J, Sampson NS, Kisker C. FadA5 a thiolase from mycobacterium tuberculosis: a steroid-binding pocket reveals the potential for drug development against tuberculosis. Structure. 2015;23(1):21–33. doi:10.1016/j.str.2014.10.010
   PubMed Web of Science ®Google Scholar
• Nesbitt NM, Yang X, Fontán P, et al. A thiolase of mycobacterium tuberculosis is required for virulence and production of androstenedione and androstadienedione from cholesterol. Infect Immun. 2010;78(1):275–282. doi:10.1128/IAI.00893-09
   PubMed Web of Science ®Google Scholar
• Tolufashe GF, Lawal MM, Govender KK, Shode FO, Singh T. Exploring the bioactivity of pentacyclic triterpenoids as potential antimycobacterial nutraceutics: insights through comparative biomolecular modelling. J Mol Graph Model. 2021;105:107900. doi:10.1016/j.jmgm.2021.107900
   PubMed Web of Science ®Google Scholar
• Chan H-C, Feng X, Ko T-P, et al. Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from Mycobacterium tuberculosis. J Am Chem Soc. 2014;136(7):2892–2896. doi:10.1021/ja413127v
   PubMed Web of Science ®Google Scholar
• Shetye GS, Franzblau SG, Cho S. New targets for growth inhibition of mycobacterium tuberculosis: why do natural terpenoids exhibit antitubercular activity? Transl Res. 2020;229:68–97. doi:10.1016/j.trsl.2020.03.007
   Google Scholar
• Jee B, Kumar S, Yadav R, Singh Y, Kumar A, Sharma N. Ursolic acid and carvacrol may be potential inhibitors of dormancy protein small heat shock protein 16.3 of Mycobacterium tuberculosis. J Biomol Struct Dyn. 2018;36(13):3434–3443. doi:10.1080/07391102.2017.1389305
   PubMed Web of Science ®Google Scholar
• Tembe N, Machaba KE, Ndagi U, Kumalo HM, Mhlongo NN. Ursolic acid as a potential inhibitor of Mycobacterium tuberculosis cytochrome bc1 oxidase-A molecular modelling perspective. J Mol Model. 2022;28(2):35. doi:10.1007/s00894-021-04993-w
   PubMed Web of Science ®Google Scholar
• Singh A, Venugopala KN, Khedr MA, et al. Antimycobacterial, docking and molecular dynamic studies of pentacyclic triterpenes from Buddleja saligna leaves. J Biomol Struct Dyn. 2017;35(12):2654–2664. doi:10.1080/07391102.2016.1227725
   PubMed Web of Science ®Google Scholar
• Pitaloka DAE, Cooper AM, Artarini AA, Damayanti S, Sukandar EY. Regulation of mitogen-activated protein kinase signaling pathway and proinflammatory cytokines by ursolic acid in murine macrophages infected with Mycobacterium avium. Infect Dis Rep. 2020;12:8717. doi:10.4081/idr.2020.8717
   PubMed Web of Science ®Google Scholar
• Saini V, Debnath SK, Maske P, Dighe V, Srivastava R. Targeted delivery of ursolic acid and oleanolic acid to lungs in the form of an inhaler for the management of tuberculosis: pharmacokinetic and toxicity assessment. PLoS One. 2022;17(12):e0278103. doi:10.1371/journal.pone.0278103
   PubMed Web of Science ®Google Scholar
• Motika SE, Hergenrother PJ. Re-engineering natural products to engage new biological targets. Nat Prod Rep. 2020;37(11):1395–1403.
   PubMed Web of Science ®Google Scholar
• Jacobo-Delgado YM, Rodríguez-Carlos A, Serrano CJ, Rivas-Santiago B. Mycobacterium tuberculosis cell-wall and antimicrobial peptides: a mission impossible? Front Immunol. 2023;14:1194923. doi:10.3389/fimmu.2023.1194923
   PubMed Web of Science ®Google Scholar
• Mopper K. Improved chromatographic separations on anion-exchange resins. II. Separation of uronic acids in acetate medium and detection with a noncorrosive reagent. Anal Biochem. 1978;86(2):597–601. doi:10.1016/0003-2697(78)90787-x
   PubMed Web of Science ®Google Scholar
• Bandžuchová L, Šelešovská R. Voltammetric determination of folic Acid using liquid mercury free silver amalgam electrode. Acta Chim Slov. 2011;58(4).
   PubMed Web of Science ®Google Scholar
• Ullevig SL, Zhao Q, Zamora D, Asmis R. Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis. Atherosclerosis. 2011;219(2):409–416. doi:10.1016/j.atherosclerosis.2011.06.013
   PubMed Web of Science ®Google Scholar
• Okumu MO, Ochola FO, Onyango AO, et al. The legislative and regulatory framework governing herbal medicine use and practice in Kenya: a review. Pan Afr Med J. 2017;28:232. doi:10.11604/pamj.2017.28.232.12585
   PubMedGoogle Scholar
• Feng Z, Wu C, Zhou J, et al. Disturbance of the intestinal microbial community by ursolic acid contributes to its function as a regulator of fat deposition. J Funct Foods. 2015;14:456–468. doi:10.1016/j.jff.2015.02.015
   Web of Science ®Google Scholar
• Kumadoh D, Ofori-Kwakye K. Dosage forms of herbal medicinal products and their stability considerations-an overview. J Crit Rev. 2017;4(4):1–8. doi:10.22159/JCR.2017V4I4.16077
   Google Scholar
• Puthli S, Vavia PR. Stability studies of microparticulate system with piroxicam as model drug. AAPS Pharm Sci Tech. 2009;10(3):872. doi:10.1208/s12249-009-9280-8
   PubMed Web of Science ®Google Scholar
• Eloy JO, Marchetti JM. Solid dispersions containing ursolic acid in Poloxamer 407 and PEG 6000: a comparative study of fusion and solvent methods. Powder Technol. 2014;253:98–106. doi:10.1016/j.powtec.2013.11.017
   Web of Science ®Google Scholar
• Ward A, Brogden RN, Heel RC, Speight TM, Avery GS. Ursodeoxycholic Acid. Drugs. 1984;27(2):95–131. doi:10.2165/00003495-198427020-00001
   PubMedGoogle Scholar
• Li J, Guo WJ, Yang QY. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J Gastroenterol. 2002;8(3):493–495. doi:10.3748/wjg.v8.i3.493
   PubMed Web of Science ®Google Scholar
• Fontanay S, Grare M, Mayer J, Finance C, Duval RE. Ursolic, oleanolic and betulinic acids: antibacterial spectra and selectivity indexes. J Ethnopharmacol. 2008;120(2):272–276. doi:10.1016/j.jep.2008.09.001
   PubMed Web of Science ®Google Scholar
• Kondo M, MacKinnon SL, Craft CC, Matchett MD, Hurta RAR, Neto CC. Ursolic acid and its esters: occurrence in cranberries and other Vaccinium fruit and effects on matrix metalloproteinase activity in DU145 prostate tumor cells. J Sci Food Agric. 2011;91(5):789–796. doi:10.1002/jsfa.4330
   PubMed Web of Science ®Google Scholar
• Kim J, Jang DS, Kim H, Kim JS. Anti-lipase and lipolytic activities of ursolic acid isolated from the roots of Actinidia arguta. Arch Pharm Res. 2009;32(7):983–987. doi:10.1007/s12272-009-1702-3
   PubMed Web of Science ®Google Scholar
• Estimation of ursolic acid from Urtica dioica L. using validated HPTLC method. Available from: https://japsonline.com/abstract.php?article_id=1254&sts=2. Accessed September 20, 2023.
   Google Scholar
• You HJ, Choi CY, Kim JY, Park SJ, Hahm KS, Jeong HG. Ursolic acid enhances nitric oxide and tumor necrosis factor-alpha production via nuclear factor-kappaB activation in the resting macrophages. FEBS Lett. 2001;509(2):156–160. doi:10.1016/s0014-5793(01)03161-1
   PubMed Web of Science ®Google Scholar
• Ikeda Y, Murakami A, Fujimura Y, et al. Aggregated ursolic acid, a natural triterpenoid, induces IL-1beta release from murine peritoneal macrophages: role of CD36. J Immunol Baltim Md. 2007;178(8):4854–4864. doi:10.4049/jimmunol.178.8.4854
   PubMed Web of Science ®Google Scholar
• Ikeda Y, Murakami A, Nishizawa T, Ohigashi H. Ursolic acid enhances cyclooxygenases and tumor necrosis factor-α expression in mouse skin. Biosci Biotechnol Biochem. 2006;70(4):1033–1037. doi:10.1271/bbb.70.1033
   PubMed Web of Science ®Google Scholar
• Ikeda Y, Murakami A, Ohigashi H. Ursolic acid promotes the release of macrophage migration inhibitory factor via ERK2 activation in resting mouse macrophages. Biochem Pharmacol. 2005;70(10):1497–1505. doi:10.1016/j.bcp.2005.08.008
   PubMed Web of Science ®Google Scholar
• Acute and genetic toxicity of ursolic acid extract from ledum pulastre L. Available from: http://www.spkx.net.cn/EN/abstract/abstract10799.shtml. Accessed June 24, 2019.
   Google Scholar
• Danielewicz A, Morze J, Przybyłowicz M, Przybyłowicz KE. Association of the dietary approaches to stop hypertension, physical activity, and their combination with semen quality: a cross-sectional study. Nutrients. 2020;12(1):39. doi:10.3390/nu12010039
   Web of Science ®Google Scholar
• Parveen A, Parveen B, Parveen R, Ahmad S. Challenges and guidelines for clinical trial of herbal drugs. J Pharm Bioallied Sci. 2015;7(4):329–333. doi:10.4103/0975-7406.168035
   PubMedGoogle Scholar
• Hussain H, Green IR, Ali I, et al. Ursolic acid derivatives for pharmaceutical use: a patent review (2012–2016). Expert Opin Ther Pat. 2017;27(9):1061–1072. doi:10.1080/13543776.2017.1344219
   PubMed Web of Science ®Google Scholar