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]. 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]. 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]. 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]. 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]. SMs, such as polyphenols, have great potential in neutralizing free radicals, and are excellent antioxidants molecules [17]. The polyphenols derived from plant crude was shown to neutralize ROS free radicals [18]. Polyphenols scavenge the singlet and triplet oxygen-generated free radicals to provide hydrogen as a donor molecule [16]. 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]. 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]. 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]. 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]. 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].

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]. 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]. 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]. Studies reveal that phenols have antimicrobial, antiviral, and anti-inflammatory actions [28,29,30]. 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]. Moreover, it has been well documented that phenolic compounds have anti-atherosclerosis and anti-cancer activity [34,35].

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]. The aqueous and ethanolic extract of Piper sarmentosum harboring antioxidant activity is reported to exhibit antitubercular activity [38]. 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]. 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 [40,41,42], 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]. 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]. 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]. Network pharmacology network procedures have increased the binding associations between ligands and their targets [46]. 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]. Hence, docking will help increase crucial knowledge about the therapeutic potential of plant metabolites [48].

As per the literature review, several reports and studies show the potential of natural products as antimycobacterial agents. Mitscher and Baker [49] accounted for various plant-derived compounds as potential antitubercular agents. Gautam et al. [50] 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]. Miryalaa et al. [51] 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