Potential Anti-Mycobacterium tuberculosis Activity of Plant SMs: Comparison
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Tuberculosis (TB) is a recurrent and progressive disease, with high mortality rates worldwide. The drug-resistance phenomenon of Mycobacterium tuberculosis is a major obstruction of allelopathy treatment. An adverse side effect of allelopathic treatment is that it causes serious health complications. The search for suitable alternatives of conventional regimens is needed, i.e., by considering medicinal plant secondary metabolites to explore anti-TB drugs, targeting the action site of M. tuberculosis.

  • plant secondary metabolites
  • drug discovery
  • multi-drug resistance
  • Tuberculosis

1. Plant Secondary Metabolites as Antioxidant and Antimycobacterial Agents

Secondary metabolites (SMs) produced by plants are defined as a different group of natural intermediary metabolic products that are not obligatorily required for the vegetative growth of plants [12][1]. These small molecules are derived mainly from the primary metabolites, in which some are nitrogen-containing alkaloids (e.g., amino acids, amines, cyanogenic glycosides, and glucosinolates), non-nitrogen compounds polyphenols, terpenoids, flavonoids, steroids, lignin, and tannins [13][2]. Since ancient times, plant extracts have been used as (an easy source of) antibiotics/antioxidants and applied as crude/extract against bacterial or fungal infections, with minimal side effects [14][3]. Out of all the plant-synthesized metabolites, alkaloids and polyphenols have potent antimicrobial and antioxidant properties. Alkaloids have a possible role in the development of antibiotics, whereas plenty of polyphenols provide a wide range of antioxidant properties that eventually establish the basis of antimicrobial activity [15][4]. Extreme environmental changes and various physiological or metabolic processes of the body can generate free radicals, which are continuously neutralized by antioxidant molecules. The optimum requirements of antioxidant molecules is required for the complete neutralization of free radicals. The excess accumulation of free radicals provokes cellular damage and can cause several fatal diseases, including cancer, diabetes, Alzheimer’s disease, and aging [16,17][5][6]. SMs, such as polyphenols, have great potential in neutralizing free radicals, and are excellent antioxidants molecules [17][6]. The polyphenols derived from plant crude was shown to neutralize ROS free radicals [18][7]. Polyphenols scavenge the singlet and triplet oxygen-generated free radicals to provide hydrogen as a donor molecule [16][5]. Several studies have proved that crude extracts of different medicinal plants have high antioxidant and antimicrobial potential.
Crude extract of flowers Wendlandia thyrsoidea, Olea dioica, Lagerstroemia speciosa, and Bombax malabaricum species showed the great potential of antioxidant and antimicrobial activity, in regard to the presence of phenolic and flavonoids [19][8]. Ziziphus lotus and Ziziphus mauritiana leave fruit and seed extract with higher phenolic flavonoids and tannins, which show tremendous antioxidant capacity and have been successfully used against different bacterial strains [20][9]. Similarly, stem bark extract of Crateva religiosa showed antimicrobial and antifungal activity due to the presence of phenolic phytochemicals. Therefore, it can be formulated for drug discovery in the future for pharmaceutical industries [21][10]. Natural bioactive compounds present in Nepeta trachonitica showed high phenolic content, and antimicrobial as well as antioxidant activity. HPLC-MS/MS data reveal that these medicinal plants have high phenolic compounds and could be a promising source of nutraceutical and drug industries [22][11]. Colorimetric, chromatographic, and spectrophotometric assays revealed that P. granatum (pomegranate) leaf extract showed a high content of total phenols, ortho-diphenols, tannins, and antioxidant capacity, making pomegranate leaf extract a valued plant source of accepted bioactive molecules for emerging beneficial food–pharma ingredients [23][12].
SMs are highly economically valuable products because of the current clinical use of drug plants. They have been used extensively as a drug, flavors, fragrances, etc. Plants synthesize a considerable number of phenols and derivatives as aromatic substances [24][13]. Thousands of terpenoids are used extensively to produce drugs synthesized from the five-carbon precursor isopentyl diphosphate. However, around 12,000 alkaloids with nitrogen atoms are biosynthesized from amino acids. Alkaloids are used as salts in medicine, such as quinine, vinblastine, and reserpine [25,26][14][15]. Currently, alkaloids are used for analgesics, anti-cancer agents, muscle relaxants, antibiotics, and sedatives.
Furthermore, around 8000 phenolic compounds are synthesized from the malonate/acetate or shikimic acid pathway [27][16]. Studies reveal that phenols have antimicrobial, antiviral, and anti-inflammatory actions [28,29,30][17][18][19]. During oxidative damage, phenolic compounds act as antioxidants and protect against the damage of cells from oxidative stress. Phenolic compounds have neuroprotective, fungicidal, and bactericidal activities [31,32,33][20][21][22]. Moreover, it has been well documented that phenolic compounds have anti-atherosclerosis and anti-cancer activity [34,35][23][24].
Plant products are virtual repositories for the development of new drugs, with minimal side effects on humans. The extensive array of phytochemicals possessing antioxidant activities is are required for the therapeutic activity of plant products against human diseases, including tuberculosis [36,37][25][26]. The aqueous and ethanolic extract of Piper sarmentosum harboring antioxidant activity is reported to exhibit antitubercular activity [38][27]. The antioxidant activity determined for different parts of the selected plant using DPPH and beta-carotene linoleic acid assay displayed substantial variations. Alcoholic extract was observed to have better antioxidant potential in comparison to aqueous extract. Recently, essential oil, and a major component, viridiflorol, derived from Allophylus edulis, have demonstrated antioxidant and anti-tuberculosis activity [39][28]. The investigation used the DPPH and ABTS assay to measure antioxidant activity of significant components and essential oils. The radical scavenging activity percentage of essential oil and viridiflorol as measured by ABTS was 44.33% and 57.55%, respectively. The antioxidant value determined by the DPPH assay, and represented as IC50, was 82.9% and 74.7%, respectively, suggesting moderate activity compared to the reference materials (butylated hydroxytoluene and ascorbic acid). The antioxidant activity antitubercular activities of plants, including Globularia alypum, Acacia catechu, Ailanthus excelsa, Aegle marmelos, Andrographis paniculata, Datura metel, and Aegiceras corniculatum, have also been registered by different researchers globally [40[29][30][31],41,42], indicating the potential opportunities of huge plant diversity in treating life-threatening diseases (e.g., tuberculosis). However, the antioxidant activity of plants varies considerably, depending on the nature of phytochemicals, the method of extraction, climatic conditions, methods of measuring antioxidant activity, and the plant parts selected. One of the major limitations of using plant products having antioxidant activity for treating tuberculosis may be the restricted synthesis of the target compound by the plant itself. However, such hurdles can be resolved to some extent by using modern genetic engineering approaches to direct the compound synthesis in the desired quantity.
Conventional methods of metabolites screening, such as high throughput screening (HTS) and virtual high throughput screening (vHTS), have been used to speed up the drug discovery for time-efficient identification of cost-effective novel and selective metabolites. However, HTS explored bulky hydrophobic metabolites poorly suited to chemical modification, requiring higher costs and time. Few vHTS success stories have been explained, identifying plant metabolites against specific virulent proteins, such as Dengue virus proteins [43][32]. Docking is the greatest tool of bioinformatics employed to determine the binding pose and binding score. Docking has been considered a “leader” in the present era, performing a range of identifications of plant metabolites to candidate leads for drug development [44][33]. The perfect binding of the compound provides the best scoring function that “implicates” in exploring the novel candidate complex and, hence, reduces the efforts needed in experimental work. The advancements in computational technology have “escorted” the synthesis of nature-based drugs, such as dasatinib and imatinib (approved by the FDA) [45][34]. Network pharmacology network procedures have increased the binding associations between ligands and their targets [46][35]. Docking has become an important methodological feature in computer added drug design (CADD). Docking is vital in determining the novel ligand from a medicinal plant for targeted proteins for structure-based drug designs [47][36]. Hence, docking will help increase crucial knowledge about the therapeutic potential of plant metabolites [48][37].
As per the literature review, several reports and studies show the potential of natural products as antimycobacterial agents. Mitscher and Baker [49][38] accounted for various plant-derived compounds as potential antitubercular agents. Gautam et al. [50][39] reported more than 200 plants having potent anti-tuberculosis activity, signifying the potential of natural products to remedy life-threatening diseases, such as TB. Drug discoveries based on computational approaches provide novel alternative tools to reduce the expensive and tedious identification of potential drug leads. Ligand-based computational screening has been used to characterize and identify new potential inhibitors and drug repurposing [44][33]. Miryalaa et al. [51][40] worked on 15 natural compounds to explore their anti-TB properties, employing in silico methods, and compared their potential with conventional drugs against TB and their respective protein targets. Interactive studies showed that glycyrrhizin, swertiamarin, and laccaic acid exhibit better binding affinity than conventional anti-TB drugs. Hence, glycyrrhizin, laccaic acid, and swertiamarin could be used to develop multi-target alternative drug candidates. Inhibition of important enzymes responsible for vital cellular functions, hence survivability of mycobacteria in the host system, is just one critical strategy used to deal with the (continuously rising) global TB incidents. In the present study, five plant secondary metabolites (alliin, aloin, octyl-β-d-glucopyranoside, oleanolic acid, and phytol) were evaluated against two standard front line anti-TB drugs, isoniazid (ISN) and ethambutol (EMB), to decipher their potential anti-tuberculosis efficacy, targeting four of the mycobacterial receptor proteins/enzymes (arabinosyltransferase C, protein kinase A, glutamine synthetase, and proteasomal ATPase) via in silico approaches.

2. Management of MDR-Mtb: A Herbal Approach

Researchers are exploring novel antimycobacterial compounds that have lesser side effects due to the development of multidrug-resistant TB and severe side effects of the synthetic drugs used for treatment. Various plants and their metabolites elicit the desired effects against the virulent disease factors under in vivo and in vitro conditions. Plant-derived chemicals proved to be the better mycobacteria-inhibitory substances, with less (or no) side effects, ensuring the fast recovery of the patients. Jimenez-Arellanes et al. [58][41] evaluated the antimycotic activity of aqueous, methanolic, and n-hexane extract of 22 different plants against M. tuberculosis H37Rv and M. avium at concentrations ranging from 50 to 200 µg/mL. In a case study, Fauziyah et al. [59][42] checked the efficiency of the combined effects of anti-tuberculosis drugs and ethanolic extract of some specific medicinal plants against multi-drug resistant Mtb isolates. They concluded that a combination of plant extracts and rifampicin achieved better effects against the rifampicin/streptomycin-resistant strain. However, they also observed the antagonistic effects with streptomycin, ethambutol, and isoniazid. Nowadays, plant extracts and their metabolites are broadly used to treat MDR in several other human pathogens, viz. Staphylococcus aureus (wound and bloodstream infections), Escherichia coli (causing urinary tract infections), and Klebsiella pneumoniae (causing pneumonia, urinary tract, and bloodstream infections). It is estimated that between 2005 and 2015, a total of 110 purified compounds and 60 plant extracts were obtained from 112 different plants having potential effectiveness against MDR pathogens [60][43].

3. Bioinformatics Opportunities for Medicinal Plant Studies

Plants have been used as therapeutic regimens since immemorial periods, and various commercially significant medicines are derived from plants. However, traditional methods used to explore plant-based regimens are timely and are highly expensive. Moreover, such extensive works have faced several problems in keeping up with the hasty advancement of high throughput technologies. In this era of high volume, high-throughput data production in life sciences—bioinformatics plays an essential role in overcoming the above-mentioned problems, with limited time and expenditure in drug design and discovery [106,107][44][45].
Nowadays, bioinformatics plays a crucial role in exploring the role of medicinal plants against various diseases, diabetes, cancer, and tuberculosis. With ever-increasing genomic and proteomic studies, it is essential to decipher the data competently. Bioinformatics plays a crucial role in exploring new genetic factors, driving the identification of several new genes and proteins. In addition, its tools have aided in explaining significant relationships between several molecular factors [108][46]. Thus, bioinformatic approaches, such as molecular docking, RMSD value, etc., help in the screening of plant metabolites, to develop drugs that target virulent factors associated with molecular pathways.

References

  1. Teoh, E.S. Secondary Metabolites of Plants. In Medicinal Orchids of Asia; Springer: Cham, Switzerland, 2016; pp. 59–73.
  2. Gorlenko, C.L.; Kiselev, H.Y.; Budanova, E.V.; Zamyatnin, J.A.A.; Ikryannikova, L.N. Plant Secondary Metabolites in the Battle of Drugs and Drug-Resistant Bacteria: New Heroes or Worse Clones of Antibiotics? Antibiototics 2020, 9, 170.
  3. Dias, D.A.; Urban, S.; Roessner, U. A Historical Overview of Natural Products in Drug Discovery. Metabolites 2012, 2, 303–336.
  4. Othman, L.; Sleiman, A.; Abdel-Massih, R.M. Antimicrobial Activity of Polyphenols and Alkaloids in Middle Eastern Plants. Front. Microbiol. 2019, 10, 911.
  5. Lü, J.-M.; Lin, P.H.; Yao, Q.; Chen, C. Chemical and molecular mechanisms of antioxidants: Experimental approaches and model systems. J. Cell. Mol. Med. 2010, 14, 840–860.
  6. Venkatachalam, R.; Kalimuthu, K.; Chinnadurai, V.; Saravanan, M.; Radhakrishnan, R.; Shanmuganathan, R.; Pugazhendhi, A. Various solvent effects on phytochemical constituent profiles, analysis of antioxidant and antidiabetic activities of Hopea parviflora. Process. Biochem. 2020, 89, 227–232.
  7. Magalhães, L.M.; Barreiros, L.; Reis, S.; Segundo, M.A. Kinetic matching approach applied to ABTS assay for high-throughput determination of total antioxidant capacity of food products. J. Food Compos. Anal. 2014, 33, 187–194.
  8. Pavithra, G.M.; Siddiqua, S.; Naik, A.S.; TR, P.K.; Vinayaka, K.S. Antioxidant and antimicrobial activity of flowers of Wendlandia thyrsoidea, Olea dioica, Lagerstroemia speciosa and Bombax malabaricum. J. Appl. Pharmac. Sci. 2013, 3, 114.
  9. Yahia, Y.; Benabderrahim, M.A.; Tlili, N.; Bagues, M.; Nagaz, K. Bioactive compounds, antioxidant and antimicrobial activities of extracts from different plant parts of two Ziziphus Mill. species. PLoS ONE 2020, 15, e0232599.
  10. Wagay, N.A.; Khan, N.A.; Rothe, S.P. Profiling of secondary metabolites and antimicrobial activity of Crateva religiosa G. Forst. bark-A rare medicinal plant of Maharashtra India. Int. J. Biosci. 2017, 10, 343–354.
  11. Köksal, E.; Tohma, H.; Kılıç, Ö.; Alan, Y.; Aras, A.; Gülçin, I.; Bursal, E. Assessment of Antimicrobial and Antioxidant Activities of Nepeta trachonitica: Analysis of Its Phenolic Compounds Using HPLC-MS/MS. Sci. Pharm. 2017, 85, 24.
  12. Yu, M.; Gouvinhas, I.; Rocha, J.; Barros, A.I.R.N.A. Phytochemical and antioxidant analysis of medicinal and food plants towards bioactive food and pharmaceutical resources. Sci. Rep. 2021, 11, 10041.
  13. Elvin-Lewis, M.; Lewis, W.H. New Concepts and Medical and Dental Ethnobotany; Dioscorides Press: Portland, OR, USA, 1995; pp. 303–310.
  14. Jordan, M.A.; Wilson, L. Microtubules as a target for anticancer drugs. Nat. Rev. Cancer 2004, 4, 253–265.
  15. Reyburn, H.; Mtove, G.; Hendriksen, I.; Von Seidlein, L. Oral quinine for the treatment of uncomplicated malaria. BMJ 2009, 339, b2066.
  16. Rodney, C.; Toni, M.; Kutchan, N.; Lewis, G. Biochemistry and Molecular Biology of Plants. In Natural Products; Buchanan, B., Gruissem, W., Jones, R., Eds.; Wiley: Rockville, MD, USA, 2000; pp. 1253–1348.
  17. Rauha, J.-P.; Remes, S.; Heinonen, M.; Hopia, A.; Kähkönen, M.; Kujala, T.; Pihlaja, K.; Vuorela, H.; Vuorela, P. Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds. Int. J. Food Microbiol. 2000, 56, 3–12.
  18. Perez, D.R.; Lim, W.; Seiler, J.P.; Yi, G.; Peiris, M.; Shortridge, K.F.; Webster, R.G. Role of Quail in the Interspecies Transmission of H9 Influenza A Viruses: Molecular Changes on HA That Correspond to Adaptation from Ducks to Chickens. J. Virol. 2003, 77, 3148–3156.
  19. Santos, A.; De Campos, R.O.; Miguel, O.G.; Filho, V.C.; Siani, A.C.; Yunes, R.A.; Calixto, J.B. Antinociceptive properties of extracts of new species of plants of the genus Phyllanthus (Euphorbiaceae). J. Ethnopharmacol. 2000, 72, 229–238.
  20. Nichenametla, S.; Taruscio, T.G.; Barney, D.L.; Exon, J.H. A Review of the Effects and Mechanisms of Polyphenolics in Cancer. Crit. Rev. Food Sci. Nutr. 2006, 46, 161–183.
  21. Prats, E.; Galindo, J.C.; Bazzalo, M.E.; León, A.; Macías, F.A.; Rubiales, D.; Jorrín, J.V. Antifungal Activity of a New Phenolic Compound from Capitulum of a Head Rot-resistant Sunflower Genotype. J. Chem. Ecol. 2007, 33, 2245–2253.
  22. Okunade, A.L.; Hufford, C.D.; Clark, A.M.; Lentz, D. Antimicrobial properties of the constituents of Piper aduncum. Phytotherapy Research: An International. J. Devoted Med. Sci. Res. Plants Plant Prod. 1997, 11, 142–144.
  23. Kato, T.; Tsuda, H.; Ishitani, Y.; Takemura, Y.; Suzuki, Y. 6-Acetyl-8-hydroxy-2,2-dimethylchromene, an Antioxidant in Sunflower Seeds; Its Isolation and Synthesis and Antioxidant Activity of Its Derivatives. Heterocycles 1997, 44, 139.
  24. Olsson, M.E.; Gustavsson, K.E.; Andersson, S.; Nilsson, A.; Duan, R.D. Inhibition of Cancer Cell Proliferation in Vitro by Fruit and Berry Extracts and Correlations with Antioxidant Levels. J. Agric. Food Chem. 2004, 52, 7264–7271.
  25. Swargiary, A.; Verma, A.K.; Singh, S.; Roy, M.K.; Daimari, M. Antioxidant and Antiproliferative Activity of Selected Medicinal Plants of Lower Assam, India: An In Vitro and In Silico Study. Anti-Cancer Agents Med. Chem. 2021, 21, 267–277.
  26. Meghashree, K.S.; Latha, K.P.; Vagdevi, H.M. Antioxidant and antitubercular activities of leaf extracts of Canthium dicoccum (Gaertn.) and Amischophacelus axillaris(L.). Indian J. Nat. Prod. Resour. 2021, 11, 244–249.
  27. Hussain, K.; Ismail, Z.; Sadikun, A.; Ibrahim, P. Antioxidant, anti-TB activities, phenolic and amide contents of standardised extracts of Piper sarmentosum Roxb. Nat. Prod. Res. 2009, 23, 238–249.
  28. Trevizan, L.N.F.; do Nascimento, K.F.; Santos, J.A.; Kassuya, C.A.L.; Cardoso, C.A.L.; do Carmo Vieira, M.; Moreira, F.M.F.; Croda, J.; Formagio, A.S.N. Anti-inflammatory, antioxidant and anti-Mycobacterium tuber-culosis activity of viridiflorol: The major constituent of Allophylus edulis (A. St.-Hil., A. Juss. & Cambess.). Radlk. J. Ethnopharmacol. 2016, 192, 510–515.
  29. Khlifi, D.; Hamdi, M.; El Hayouni, A.; Cazaux, S.; Souchard, J.P.; Couderc, F.; Bouajila, J. Global Chemical Composition and Antioxidant and Anti-Tuberculosis Activities of Various Extracts of Globularia alypum L. (Globulariaceae) Leaves. Molecules 2011, 16, 10592–10603.
  30. Tawde, K.; Gacche, R.; Pund, M. Evaluation of selected Indian traditional folk medicinal plants against Mycobacterium tuberculosis with antioxidant and cytotoxicity study. Asian Pac. J. Trop. Dis. 2012, 2, S685–S691.
  31. Janmanchi, H.; Raju, A.; Degani, M.; Ray, M.; Rajan, M. Antituberculosis, antibacterial and antioxidant activities of Aegiceras corniculatum, a mangrove plant and effect of various extraction processes on its phytoconstituents and bioactivity. S. Afr. J. Bot. 2017, 113, 421–427.
  32. Qamar, M.T.U.; Maryam, A.; Muneer, I.; Xing, F.; Ashfaq, U.A.; Khan, F.A.; Anwar, F.; Geesi, M.H.; Khalid, R.R.; Rauf, S.A.; et al. Computational screening of medicinal plant phytochemicals to discover potent pan-serotype inhibitors against dengue virus. Sci. Rep. 2019, 9, 1433.
  33. Kitchen, D.B.; Decornez, H.; Furr, J.R.; Bajorath, J. Docking and scoring in virtual screening for drug discovery: Methods and applications. Nat. Rev. Drug Discov. 2004, 3, 935–949.
  34. Ghosh, A.K.; Gemma, S. Structure-Based Design of Drugs and Other Bioactive Molecules: Tools and Strategies; John Wiley & Sons: New York, NY, USA, 2014.
  35. Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol. 2008, 4, 682–690.
  36. Sandeep, G.; Nagasree, K.P.; Hanisha, M.; Kumar, M.M.K. AUDocker LE: A GUI for virtual screening with AUTODOCK Vina. BMC Res. Notes 2011, 4, 445.
  37. Singh, H.; Bharadvaja, N. Treasuring the computational approach in medicinal plant research. Prog. Biophys. Mol. Biol. 2021, 164, 19–32.
  38. Mitscher, L.A.; Baker, W. Tuberculosis: A search for novel therapy starting with natural products. Med. Res. Rev. 1998, 18, 363–374.
  39. Gautam, R.; Saklani, A.; Jachak, S.M. Indian medicinal plants as a source of antimycobacterial agents. J. Ethnopharmacol. 2007, 110, 200–234.
  40. Miryala, S.K.; Basu, S.; Naha, A.; Debroy, R.; Ramaiah, S.; Anbarasu, A.; Natarajan, S. Identification of bioactive natural compounds as efficient inhibitors against Mycobacterium tuberculosis protein-targets: A molecular docking and molecular dynamics simulation study. J. Mol. Liq. 2021, 341, 117340.
  41. Jimenez-Arellanes, A.; Meckes, M.; Ramírez, R.; Torres, J.; Luna-Herrera, J. Activity against multidrug-resistantMycobacterium tuberculosis in Mexican plants used to treat respiratory diseases. Phytotherapy Res. 2003, 17, 903–908.
  42. Fauziyah, P.N.; Sukandar, E.Y.; Ayuningtyas, D.K. Combination Effect of Antituberculosis Drugs and Ethanolic Extract of Selected Medicinal Plants against Multi-Drug Resistant Mycobacterium tuberculosis Isolates. Sci. Pharm. 2017, 85, 14.
  43. Subramani, R.; Narayanasamy, M.; Feussner, K.-D. Plant-derived antimicrobials to fight against multi-drug-resistant human pathogens. 3 Biotech 2017, 7, 172.
  44. Romano, J.D.; Tatonetti, N.P. Informatics and Computational Methods in Natural Product Drug Discovery: A Review and Perspectives. Front. Genet. 2019, 10, 368.
  45. Sharma, V.; Sarkar, I.N. Bioinformatics opportunities for identification and study of medicinal plants. Brief. Bioinform. 2013, 14, 238–250.
  46. Babar, M.; Zaidi, N.-U.-S.S.; Pothineni, V.R.; Ali, Z.; Faisal, S.; Hakeem, K.; Gul, A. Application of Bioinformatics and System Biology in Medicinal Plant Studies. In Springer Protocols Handbooks; Springer: Cham, Switzerland, 2017; pp. 375–393.
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