Phytochemicals as Antimicrobials: Comparison
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Among all available antimicrobials, antibiotics hold a prime position in the treatment of infectious diseases. However, the emergence of antimicrobial resistance (AMR) has posed a serious threat to the effectiveness of antibiotics, resulting in increased morbidity, mortality, and escalation in healthcare costs causing a global health crisis. The overuse and misuse of antibiotics in global healthcare setups have accelerated the development and spread of AMR, leading to the emergence of multidrug-resistant (MDR) pathogens, which further limits treatment options. This creates a critical need to explore alternative approaches to combat bacterial infections. Phytochemicals have gained attention as a potential source of alternative medicine to address the challenge of AMR. Phytochemicals are structurally and functionally diverse and have multitarget antimicrobial effects, disrupting essential cellular activities.

  • antimicrobial resistance
  • antimicrobials
  • multidrug resistance

1. Antimicrobial Resistance Modulation via Natural Products

Infectious diseases constitute one of the major contributing factors towards high mortalities worldwide, and the slow discovery of novel antibiotics has created a void in the available treatment options, which has necessitated the need to revisit and explore natural resources [84][1]. In the pre-antibiotic era, since people were completely dependent on natural resources for all their needs, including medicines, these resources significantly contributed to the treatment of various diseases. Among natural products, microbes and plant products hold prime importance. Since the discovery rate of microbially derived antimicrobials is at its lowest since the golden age of antimicrobials and the emergence of AMR has further narrowed down the treatment options, exploration of alternative medicine based on plant products has become necessary [85][2]. Plants, being easily available and easy to handle, were the first to be used as treatment options for infectious diseases, which continues even today in many tribal communities as an alternative to modern antibiotics. Plants produce hundreds and thousands of structurally and functionally diverse phytochemicals that exert a multitargeted impact on pathogenic microbes, ensuring their death and no further resistance development [13,14,85,86][2][3][4][5]. Given the availability of huge phytochemical reserves in the plant kingdom, exploring them for antimicrobial agents seems promising.

1.1. Multiple-Compound Synergy vs. Single-Compound Therapy

Plants, as living organisms, are complex systems that are self-organising and environmentally adaptive. These complex adaptive traits are a function of the complex chemical matrix that works in synergy to give rise to complex systems such as plants [13][3]. Plants thrive in diverse habitats, which are vulnerable to pathogenic attacks, and unlike animals, plants do not possess an adaptive immune system. Therefore, they produce structurally and functionally diverse chemicals known as plant secondary metabolites (PSM), which are functionally so diverse that they not only kill pathogenic microbes but also ensure that there is no resistance development anytime soon [87,88,89][6][7][8]. For instance, a recent study conducted on Artemisia annua L. crude extracts (herbal tea) and pure artemisinin resulted in a 6–18-fold reduction in plasmodial IC50 in the case of crude extract as compared to purified artemisinin [90][9]. This phenomenon is explained by the existence of interacting and potentiating compounds in the crude extract that enhance its activity in comparison to the single active compound [87,88,89][6][7][8]. Further insights are needed to decipher the interaction of phytocompounds in a mixture to devise efficient antimicrobials from plant secondary metabolites.

1.2. Plant Secondary Metabolites as Antimicrobials

Since the advent of antibiotics in 1930, many classes of microbe-derived antimicrobials have been introduced in the antibiotics market. However, over time, cross-resistance to these antibiotics has proved to be a grave issue for infection treatment worldwide, particularly in developing countries [7,8][10][11]. Over-the-counter availability and ignorant consumption of antibiotics have significantly contributed to the evolution of multidrug resistance among microbes [7,25][10][12].
With the growing antimicrobial resistance in microbes, recent years have shown a great shift towards alternative therapies, compared to conventional antibiotics, including increasing use of natural products. There has been a growing need for the use of alternate therapies, especially those derived from plants [91,92,93,94][13][14][15][16]. Plant metabolites are being used directly or as precursors for new synthetic products [95][17]. Due to their having almost no side effects, most people worldwide prefer biological components for maintaining their health [96][18]. The first phytocompound used as medicine was morphine, which was discovered from opium poppy (Papaver somniferum L.) [97][19]. Since then, chemicals found in plants that have the potential to treat disease have been widely used, usually in crude forms. However, the period after the 1980s saw a dramatic shift in pharmaceutical firms towards synthetic chemistry or, most appropriately, towards combinatorial chemistry for more efficient and economical drug development options [98,99][20][21]. The effectiveness of plant secondary metabolites as herbal formulations and antimicrobial agents has prioritized the use of phytocompounds in drug development against multidrug-resistant microbes [15,100,101][22][23][24]. However, despite extensive research, the Food and Drug Administration (FDA) has authorised only a few phytochemicals, such as capsaicin, codeine, paclitaxel, reserpine, and colchicine, as antimicrobial agents against drug-resistant microbes [10,57][25][26]. Crude methanolic extracts of several plants such as lemongrass, neem, Aloe vera L., oregano, rosemary, thyme, and tulsi have demonstrated effective antimicrobial activities, which were attributed to the presence of flavonoids and tannins in their crude extracts [102][27].
Apart from crude extracts, which represent the synergistically cooperating mixture of various phytochemicals, several active formulae in their purified states have shown activity against MDR pathogens along with their molecular targets. To name a few, baicalein found in Thymus vulgaris L., Scutellaria baicalensis Georgi, and Scutellaria lateriflora L. has shown antimicrobial activity against MRSA, which can be attributed to its potential to inhibit the NorA efflux pump of MRSA [103,104][28][29]. Berberine, isolated from Berberis L. sp., has demonstrated antimicrobial activity by inhibiting bacterial gyrase/topoisomerase, RNA polymerase, and cell division [105][30]. Magnolol, isolated from the bark of Magnolia officinalis Rehder & E.H.Wilson, has demonstrated synergistic activity with meropenem by inhibiting New Delhi metallo-β-lactamase (NDM-1), thereby restoring its activity against NDM-1 expressing Escherichia coli [106][31]. Plasmid-mediated antimicrobial resistance is one of the underlying reasons for bacteria exhibiting resistance behaviour in response to antibiotics. Several phytochemicals, such as 8-epidiosbulbin-E-acetate isolated from Dioscorea bulbifera Russ. ex Wall., have been reported to possess curing efficiency against resistance plasmids of Enterococcus faecalis, Shigella sonnei, Pseudomonas aeruginosa, and Escherichia coli [107][32].

1.2.1. Alkaloids

Alkaloids are heterocyclic nitrogenous compounds, biosynthetically derived from amino acids, and show variability in chemical structures [108,109][33][34]. The activity of alkaloids against microbial infections is mainly attributed to their inhibitory effects against efflux pumps. Many alkaloid compounds have been reported to have marked significance in the treatment of microbial infections.
Berberine is an isoquinoline alkaloid found in the bark of the stem and roots of Berberis L. species and is found to possess antimicrobial activity against various microbes including bacteria, fungi, protozoa, and viruses [92][14]. The mode of antimicrobial activity of berberine is attributed to DNA intercalation, inhibition of RNA polymerase, and inhibition of DNA gyrase and Topoisomerase IV [57,110][26][35]. Further, it was also shown to inhibit FtsZ (filamenting temperature-sensitive mutant Z) protein, thus inhibiting cell division [57,92][14][26].
Another isoquinoline alkaloid, ungeremine, isolated from methanolic fractions of Pancratium Illyricum L., was found to possess significant antibacterial activity, as it inhibits bacterial topoisomerase, leading to DNA cleavage [92,111][14][36].
Piperine, isolated from Piper nigrum L. (black pepper) and Piper longum L. (Indian long pepper), is a piperidine alkaloid that has demonstrated antimicrobial activity against Staphylococcus aureus and synergistically reduced the minimum inhibitory concentration (MIC) values when administered along with fluoroquinolone antibiotics [112][37]. Its inhibitory effect against MRSA was due to the inhibition of NorA efflux pumps. The synergism of piperine and aminoglycoside antibiotic, namely gentamicin when administered as nano-liposomes, demonstrated high effectiveness against MRSA infection [92,113,114][14][38][39]. Apart from naturally occurring piperine, its synthetic analogues such as 5-(2,2-dimethyl-chroman-6-yl)-4-methyl-penta-2,4-dienoic acid ethyl ester and 5-(2,2-Dimethyl-chroman-6-yl)-4-methyl-2E,4E-pentadienoic acid pyrrolidine were also found to inhibit NorA efflux pumps expressed in Staphylococcus aureus [27,115][40][41].
Maculine, kokusagine, and dictamine belong to the quinolone class of alkaloids, are primarily found in the stem bark of Teclea afzelii Engl., and have demonstrated significant antimicrobial activity. The mode of action of both natural and synthetic quinoline alkaloids involves the inhibition of type II topoisomerase leading to the inhibition of DNA replication [116][42]. Reserpine, isolated from Rauvolfia serpentina (L.) Benth. ex Kurz, is an indole alkaloid, was found to inhibit efflux pumps, and was reported to decrease the fluoroquinolone resistance in Stenotrophomonas maltophilia, which was earlier resistant due to over-expression of efflux pumps [117][43].
The steroidal alkaloids tomatidine and conessine possess antibacterial activities due to potentiating other antibiotics when used in synergism. When used alone or in conjunction with aminoglycoside antibiotics, tomatidine, which is derived from plants belonging to the Solanaceae family such as tomato, brinjal, and potato, has demonstrated antimicrobial activity against Staphylococcus aureus [118][44]. It could be used as a potentiator for many antibiotics of different classes, such as ampicillin, cefepime, ciprofloxacin, and gentamicin, when used to treat infections caused by Pseudomonas aeruginosa, Staphylococcus aureus, or Enterococcus faecalis bacteria [92][14]. Conessine has demonstrated synergistic activity when administered along with antibiotics [92,119][14][45]. It has demonstrated resistance-modifying activity against Acinetobacter baumannii by inhibiting the AdeIJK efflux pump [120][46].
Sanguinarine is an alkaloid constituent of many plants including Argemone Mexicana L., Chelidonium majus L., Macleaya cordata (Willd.) R.Br., and Sanguinaria canadensis L. It has shown antibacterial activity against MRSA strains, and its mechanism involves cell lysis brought about by the release of autolytic enzymes [121][47]. It was also reported to act as an effective inhibitor of bacterial replication and transcription [122][48]. Furthermore, Sanguinarine exhibits potent antimycobacterial activities against Mycobacterium aurum and Mycobacterium smegmatis [123][49].
Caffeine, a xanthine alkaloid, has shown anti-quorum-sensing activity against Pseudomonas aeruginosa by interacting with the quorum-sensing proteins such as LasR and LasI and down-regulating the secretion of its virulence factors [124][50].
Plant secondary metabolites (PSM) can have additive, antagonistic, or synergistic effects on conventional antibiotics. However, the synergistic effect of PSM with antibiotics is the most preferable interaction in terms of antimicrobial therapies. Two drugs are said to be synergistic when the combined effect they produce is greater than the sum of their individual effects (the phenomenon where the combined effect equals the sum is known as additive effect). Synergistic interaction between two drugs is preferred in the case of antimicrobial therapies, as it allows the use of lower doses of the combination constituents, which not only reduces the duration of antimicrobial therapy but also reduces the chances of dose-dependent toxicity, if any [89][8]. Many PSMs have been found to have synergistic activities with antibiotics against pathogenic infections. Chanoclavine, an ergot alkaloid, has shown synergistic activity with tetracycline against resistant strains of Escherichia coli [125][51]. Furthermore, 1-4-napthoquinone has demonstrated antimicrobial activity for both Gram-negative and Gram-positive bacteria [126][52]. It has exhibited synergistic behaviour with carbapenems (imipenem) and cephalosporins (cefotaxime and cefuroxime) against MRSA [13,127][3][53].
Alkaloids found in the plant kingdom are structurally very diverse and thus show variability in scale and mode of activity. However, irrespective of the diversification in the mechanism of action, plant alkaloids can be developed into potent antimicrobials, which would not only revive the treatment options but also ensure the development of further resistance is prevented.

1.2.2. Phenols

Due to their wide range of pharmacological activities and strong pharmacological effects, plant phenolics are recognised as important bioactive compounds. Plant-derived phenols can be found in simple or polymerized forms and contain an aromatic ring structure with one or more hydroxyl groups. Plant phenolics are categorized into many classes such as simple phenols, phenolic acids, quinones, flavonoids, and tannins. Phenols have proven to be potent against a wide range of diseases such as bacterial infections, cancers, diabetes, and cardiovascular diseases [137,138,139,140][54][55][56][57]. Plant phenolics have exhibited antimicrobial potency against a variety of microbes by sensitizing them against antibiotics and tuning down the efflux pump activity by acting as potent efflux pump inhibitors.
Simple phenols such as catechol and pyrogallol, which are allelochemicals synthesized by plants, have shown antibacterial activities against three bacterial strains: Corynebacterium xerosis, Pseudomonas putida, and Pseudomonas pyocyanea. Moreover, catechol was found to have an antifungal effect on Fusarium oxysporum and Penicillium italicum [141][58]. Furthermore, 4-(4-Hydroxyphenethyl) phen-1,2-diol (2a), a derivative of catechol and pyrogallol, was found to inhibit Helicobacter pylori urease enzyme [142][59]. Resorcinol, isolated from Ainsliaea bonatii Beauverd, was found to be effective against MRSA and ESBL Staphylococcus aureus. The mode of action was reported to be cell wall disintegration, leading to increased permeability and leakage of intracellular constituents, negatively influencing gene expression and leading to decreased protein synthesis [143][60]. Resveratrol, a natural phenolic compound, exhibited efflux pump inhibitory activity against various bacterial strains such as CmeABC, a multidrug efflux system of Campylobacter jejuni, and efflux pumps of Mycobacterium smegmatis [144][61].
Gallic acid and ferulic acid have been reported to possess significant antimicrobial activities against Escherichia coli, Staphylococcus aureus, Listeria monocytogenes, and Pseudomonas aeruginosa, and the mode of action was found to be the disruption of cell membrane via changes in membrane potential [145][62]. Furthermore, 3-p-trans-coumaroyl-2-hydroxyquinic acid, isolated from Cedrus deodara (Roxb. ex D.Don) G.Don, has shown effective antibacterial activity against Staphylococcus aureus, and the mechanism of action involves damage to cytoplasmic membrane due to membrane hyperpolarization and loss of membrane integrity, which results in subsequent discharge of intracellular constituents [146][63]. Chebulinic acid, primarily isolated from Terminalia chebula Retz., has been reported to inhibit DNA gyrase of quinolone-resistant Mycobacterium tuberculosis [147][64]. However, the whole study was in silico based, and further insights are needed to unravel its significance as a DNA gyrase inhibitor and anti-tuberculosis agent [92][14].
Quercetin and apigenin belong to the flavonoid class of plant phenols, which act as antibacterial agents against Helicobacter pylori and Escherichia coli, and the mechanism of action involves inhibition of d-alanine:d-alanine ligase, an enzyme important for bacterial cell wall assembly [148][65].
Baicalein is a flavone, primarily isolated from Scutellaria baicalensis Georgi, Scutellaria lateriflora L., and Thymus vulgaris L. It inhibits NorA efflux pumps, thus increasing the efficacy of antibiotics such as β-lactams, ciprofloxacin, and tetracycline against methicillin-resistant Staphylococcus aureus. When co-administered with tetracycline, baicalein also shows a synergistic effect against Escherichia coli due to inhibition of the efflux pump [103,104][28][29].
Biochanin A, an isoflavone, has inhibitory activity against MRSA and has been found to inhibit MRSA efflux pumps by reducing NorA protein expression [149][66].
Kaempferol, an active flavonoid, has shown potent antimicrobial activity against triazole-resistant Candida albicans and MRSA [150,151][67][68]. Kaempferol inhibits NorA efflux pump, as does its naturally occurring glycoside derivative, kaempferol rhamnoside, which has a potentiating effect on ciprofloxacin against NorA pumps of Staphylococcus aureus [150][67].
Catechins found in green tea form the basis of the antimicrobial potential of tea extracts. The antimicrobial activity of catechins is attributed to their hydrogen peroxide generation, which ultimately leads to bacterial cell membrane damage [152][69]. Epigallocatechin gallate (EGCG) is yet another phenolic compound that exhibits antimicrobial activity against MRSA by inhibiting NorA efflux pump [27,92,98][14][20][40]. EGCG has been shown to inhibit DNA gyrase by blocking its β-subunit at the ATP binding site, bacterial efflux pump, and inhibition of chromosomal penicillinases, owing to its multitargeted action against pathogenic microbes [153][70].
Tannins have been reported to have much more effective antimicrobial action on Gram-positive bacteria than Gram-negative ones. This difference in activity is because of the mode of action of tannins. Tannins pass through the bacterial cell wall and interfere with the metabolism of bacterial cell. On the other hand, double-layered cell walls of Gram-negative bacteria offer much resistance for the tannins to pass through, hence the reduced activity [154][71]. Curcumin, abundantly found in Curcuma longa L., has demonstrated antimicrobial activity against Escherichia coli and Staphylococcus aureus. The antibacterial activity is attributed to its capacity to damage the membrane by penetrating through the bilayer and increasing the membrane permeability [155][72].

1.2.3. Organosulfur Compounds

Organosulfur compounds are sulfur-containing organic molecules that are responsible for the strong aromas of Allium vegetables such as onions and garlic. They are also present in cruciferous vegetables such as cabbage and broccoli. Several organosulfur compounds such as allicin, ajoene, dialkenyl sulfides, S-allyl cysteine, and isothiocyanates were found to be effective against both Gram-positive as well as Gram-negative bacteria [168,169,170,171][73][74][75][76]. Investigations have revealed that high-concentration polysulfide-containing plants possess broad-spectrum antibacterial activities [172][77].
Diallyl thiosulfinate, commonly known as ‘allicin’, is an organosulfur compound that is isolated from Allium sativum L. Its antibacterial action has been seen against a variety of pathogenic microbes, including MRSA, Pseudomonas aeruginosa, Streptococcus agalactiae, Staphylococcus epidermidis, and oral pathogens that can cause periodontitis [168,173][73][78]. Allicin mainly causes the suppression of sulfhydryl-dependent enzymes, including alcohol dehydrogenase, thioredoxin reductase, and RNA polymerase, which is the primary mechanism of its antibacterial activity. Further, allicin has also been shown to partially inhibit protein and nucleic acid synthesis [174,175][79][80].
Ajoene, another organosulfur compound, is not as functionally diverse as allicin. However, it exhibits potency against both Gram-positive as well as Gram-negative bacteria along with some fungal strains, including Aspergillus niger and Candida albicans. The mechanism of action is the same as that of allicin, as ajoene is also a sulfhydryl-dependent enzyme inhibitor [168][73].
Isothiocyanates (ITCs) are exclusively abundant in members of the family Brassicaceae Burnett. such as broccoli, cabbage, cauliflower, and mustard, and they show activity against oral pathogens as well as Helicobacter pylori [170,176,177][75][81][82]. The antimicrobial mechanism of ITCs is not fully understood yet. However, it is speculated that their activity might be due to their reaction with cellular proteins and enzymes, which then hamper the biochemical processes inside the cell. Due to the high electrophilicity of an ITC carbon atom, it can react with amines, thiols, and hydroxyl groups of cellular proteins [170][75].

1.2.4. Terpenes

Terpenes are aromatic compounds found in many plants and are responsible for the characteristic smell of many plants, such as cannabis, pine, and lavender, as well as fresh orange peel. Terpenes are commonly distributed in nature, in nearly all living forms, and perform a variety of functions in cells. Apart from being primary structural components of cells (cholesterol and steroids in cellular membranes), they also act as functional molecules such as carotenoids, quinones, and retinal in photosynthesis, electron transport, and vision, respectively [183][83].
Normally, terpenes have demonstrated more potent activity for Gram-positive than Gram-negative bacteria and bring about their antibacterial effects mainly via lipophilic features. Monoterpenes change membrane structure by changing their composition, which increases fluidity and permeability and causes changes in the topology of membrane proteins, causing disruptions throughout the respiratory chain [184][84]. Carvacrol is commonly found in the essential oils of Thymus vulgaris L., Lepidium flavum Torr., Citrus aurantium (Spreng.), Balle ssp. Bergamia, and Origanum vulgare L., among other plants. It has demonstrated antibiofilm development activity against Staphylococcus aureus and Salmonella typhimurium and is reported to have activity against tobacco mosaic virus and cucumber mosaic virus [185,186][85][86]. Carvacrol has also been shown to be effective against food-borne pathogens such as Escherichia coli, Salmonella, and Bacillus cereus [124][50].
Thymol, found as an essential oil component of Thymus vulgaris L, has shown antibacterial effects on tetracycline-resistant Salmonella typhimurium and Escherichia coli, penicillin-resistant Staphylococcus aureus, and erythromycin-resistant Streptococcus pyogenes. The mechanism of action, as per many studies, involves disintegration of cell membranes [187,188][87][88].
Ursolic acid, a pentacyclic triterpene, possess broad-spectrum antibacterial activity. It was shown that ursolic acid has disorganising effects on Escherichia coli membrane [189][89]. Eugenol and cinnamaldehyde are yet more important terpenes present in plant essential oils and have shown activity against a wide range of pathogens including Helicobacter pylori, causing damage to the cell membrane [190,191][90][91]. Eugenol has been shown to inhibit biofilm formation by MRSA and MSSA clinical strains as well as the synthesis of virulence factors by Pseudomonas aeruginosa [190,192][90][92]. The mechanism of eugenol action involves damage to bacterial membrane, followed by leakage of cellular contents. As for cinnamaldehyde, the compound works by damaging the membrane, decreasing the membrane potential, and alterations in metabolic activity [193][93].

2. Himalayan Medicinal Plants as a Reservoir of Phytochemicals for Novel Antimicrobial Drug Discovery

2.1. Plant Diversity of Indian Himalayas

The Indian Himalayas are one of the thirty-six designated biodiversity hotspots globally [16][94]. Spread over an area of 3000 km from Northern Pakistan to North East India, the region spans incredible variations in climate across its course. Geographically, the entire mountain range has been divided into two regions: the Eastern Himalayas, which span from Nepal, Tibet, Bhutan, West Bengal, Assam, and Arunachal Pradesh to Northern Myanmar; and the Western Himalayas, which include parts of Uttarakhand, Northwest Kashmir, and Northern Pakistan [16][94].
The Indian Himalayan region is home to an estimated 10,000 species of vascular plants, out of which 3160, accounting for almost 1/3rd of the total plant species found, are endemic to the region [197][95]. Additionally, 71 genera and 5 plant families are also endemic to the area. The endemic plant families include Trochodendraceae Eichler, Hamamelidaceae R. Br., Butomaceae Mirb., and Stachyuraceae J. Agardh. The largest family of flower-bearing plants in the region is Orchidaceae Juss., with an estimated number of 750 species [197][95]. Among the 5725 species of angiosperms endemically found in India, 3471 species are hosted by the Himalayas themselves. Moreover, among the 147 genera of angiosperms that are endemic to India, 71 are found exclusively in the Himalayan region [198][96]. The Himalayas host all the conifer (gymnosperms) flora of India except for Podocarpus wallichianus C.Presl and Podocarpus neriifolius D.Don, which are found in peninsular India and the Andamans, respectively. Among the gymnosperm shrubs, Ephedra gerardiana Wall. ex Klotzsch & Garcke is exclusively distributed in the Himalayas and is highly revered as a medicinal plant due to its alkaloid ephedrine [199][97]. Among the pteridophytes, the Eastern Himalayas contain about 847 taxa in 179 genera, followed by the Western Himalayas, which contain 340 taxa in 101 genera of pteridophytes [200][98]. Of the 2000 species of mosses (bryophyte) found in India, the Eastern Himalayas contain 1030 species and 751 species are distributed in the Western Himalayas [201][99]. About 30% of the total liverwort population is maximally distributed in the Eastern Himalayas followed by the Western Himalayas and the Western Ghats [202][100].

2.2. Medicinal Plant Resources of Himalayas and Alternate Systems of Medicine

The Indian subcontinent possesses one of the oldest and most well-structured medical systems, which originated more than 5000 years ago [203][101]. The vast information on medicine is backed by different traditional medicinal practices such as Ayurveda and Unani and various literary manuscripts such as Charak Samhita, Sushruta Samhita, Dhanvantri, and Nighatu [204,205][102][103]. These scriptures provide a solid foundation for traditional medicinal practices in India [206][104]. Various communities in India, both tribal and urban, rely on traditional medicine, and it has long been an important element in the treatment of diseases and disorders. Around 25000 phytocompounds are used as herbal formulations in rural Indian traditional medicine, particularly in tribal populations [207][105]. Of these phytocompounds, only 5–10% have been confirmed scientifically [208][106]. Due to the rising interest in adopting traditional medicine globally, government institutions in India have made attempts to validate the therapeutic efficiency of the drugs used in traditional medicine [209][107]. The Himalayan region is home to many endemic human populations, and due to the remoteness of the area, the people have been relying on forest products for multiple needs, including the ethnomedicinal use of plants for disease treatment, as a result of which the people of the Himalayas have a strong belief in traditional herbal medicine [210,211][108][109].
The Indian Himalayas foster around 10,000 species of higher plants, of which 1748 species reportedly have medicinal properties [18,19][110][111]. Medicinal plants of the region have played fundamental roles in the disease treatment of the people living in and around the Himalayan mountain range [19][111]. The vegetation of the area is determined by the climate and weather conditions of the area. For instance, the North-Western Himalayas, including the areas of Ladakh and Gilgit, have weather conditions ranging from mild summers to severely cold winters, and the medicinal flora are represented by Achillea millefolium L., Bunium persicum (Boiss.) B. Fedtsch., Picrorhiza kurroa Royle ex Benth., Juniperus communis L., and Ephedra gerardiana Wall. ex Klotzsch & Garcke [212][112]. The Western Himalayan region, including Jammu and Kashmir, Himachal Pradesh, Garhwal, and Kumaon Himalaya, experiences warm humid summers and cold humid winters, and the medicinal flora are primarily represented by Saussurea costus (Falc.) Lipsch., Colchucum luteum Baker, Atropa acuminata Royle ex Lindl., and Physochlaina praealta (Decne.) Miers. On the other hand, the Eastern Himalayas, comprising areas such as Darjeeling, parts of Assam, Sikkim, and Arunachal Pradesh, are characterized by warm summer and cool winter. Hence, the vegetation is represented predominantly by Aquilaria malaccensis Benth., Coptis teeta Wall., and Panax pseudoginseng Wall. [16][94]. In the adjoining Himalayan region of north-western Pakistan, medicinal plants such as Berberis lyceum Royle, Achillea millefolium L., Bergenia ciliata (Royle) A.Braun ex Engl., and Aloe vera L. have been reported to be used against urinary tract infections due to their antimicrobial activity against Staphylococcus aureus and Escherichia coli [140][57]. Further, medicinal plants such as Impatiens glandulifera Royle, Artemisia scoparia Waldst. & Kit., Ageratum conyzoides L., and Achillea millefolium L. have been reported to be used as treatment options for various ailments such as urinary tract infections, cardiac diseases, baldness, abortion and miscarriage jaundice, hepatitis, typhoid, fever, and tuberculosis [211][109].
In India, around 17,000 species of higher plants have been discovered, of which 7500 plant species have been found to have medicinal properties, which is the highest total-plants-to-medicinal-plants proportion so far reported [16,17][94][113]. The maximum population of medicinal plants (1717 species) has been reported at an elevation of 1800 m. Traditional medical practices of the Indian subcontinent use many medicinal plants, and Ayurveda alone has reported 2000 medicinal plant species. One of the oldest written documents on herbal medicine, the Charak Samhita, documents 340 herbal drug productions and their aboriginal uses [213][114]. The rich diversity of medicinal plants in the Himalayas gave rise to the traditional medicine practices such as Ayurveda and Unani. Apart from the widely followed systems of traditional medicine, various local systems of practices based on the cultural demography have also developed. For instance, the traditional healers of Ladakh region (North-Western Himalayas) are known as “amchies”, those who practice in Kashmir Valley are known as “hakeems”, and those in Jammu are called “veds”. These traditional practices came into existence primarily because of the absence of modern medicine in past times and are still carried forward to this date as a part of tradition [214][115].

3. Antimicrobial Profile of Himalayan Medicinal Plants

One of the main causes of clinical mortality in humans has been infectious diseases. Moreover, with the emergence of multidrug-resistant microbes, the existing antimicrobial therapies have been rendered inactive, which has made the development of new antimicrobials necessary [26][116]. In the pursuit of novel antimicrobials, plants blessed with a plethora of secondary metabolites offer a vast array of phytochemicals to be screened for novel antimicrobials and developed into new antimicrobial therapies [102][27]. Humans have been using plants for remedial measures against various ailments for generations, as a result of which many forms of traditional medicines came into existence. These herbal medicines constitute a major part of traditional medical practices [206,211][104][109]. The Indian Himalayan region comprises 31% native, 15.5% endemic, and 14% threatened plant species [204][102]. The floristically rich Himalayan region is a potential source of many drug-yielding plants [215][117]. Many of the medicinal plants in the Himalayas have shown potent antimicrobial activity against pathogenic microbes [14,216][4][118].
Angiosperms such as Acorus calamus L. (asarone), Aegle marmelos (L.) Corrêa (rutacin), Arnebia euchroma (Royle ex Benth.) I.M.Johnst. (shikonin), Berberis L. sp. (berberine), Callicarpa macrophylla Vahl (sesquiterpenes and triterpenes), Curcuma caesia Roxb. (cinnamate), Hedychium spicatum G.Lodd. (limonene, linalool), Inula racemosa Hook.f. (isoalantolactone), Jasminum officinale L. (jasminol, lupeol), Myrsine semiserrata Wall. (embelic acid), Nardostachys jatamansi (D.Don) DC. (jatamansic acid), and Piper longum L. (piperine) are a few of the candidate phytochemicals that have shown potent antimicrobial activities. Prunus cornuta (Wall. ex Royle) Steud. and Quercus semecarpifolia Sm. have shown antibacterial activity against Acinetobacter baumannii, Salmonella enterica, and Escherichia coli [212][112].
Gymnosperm plants such as the species of Cycas L. and Ginkgo L., Sabina chinensis (L.) Antoine, Cedrus deodara (Roxb. ex D.Don) G.Don, Pinus bungeana Zucc. ex Endl., Platycladus orientalis (L.) Franco, and Torreya grandis Fortune ex Lindl. have shown antimicrobial activities. The essential oil ‘turpentine’ obtained from plants such as Abies balsamea (L.) Mill., Pinus brutia Ten., and Pinus roxburghii Sarg. has demonstrated antimicrobial activity against MRSA [199][97].
Among the pteridophytes, Adiantum philippense L., Adiantum caudatum L., Adiantum incisum C. Presl., and Adiantum venustum D.Don have shown strong antimicrobial activity against pathogens, causing food-borne infections [217][119]. Members of the genus Dryopteris have shown activity against Pseudomonas aeruginosa [218][120]. Equisetum arvense L. has shown activity against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella enteritidis, Aspergillus niger, and Candida albicans [219][121].
Many bryophytes have been used traditionally for inflammation, heart disease, digestive problems, lung, and skin diseases [220][122]. However, some bryophytes (mosses) have shown antimicrobial properties [221][123]. Marchatia polymorpha L. has demonstrated antimicrobial activity against Escherichia coli, Staphylococcus aureus, Proteus mirabilis, Aspergillus niger, Aspergillus flavus, and Candida albicans [222][124]. Some antimicrobial bioactive compounds such as polygodial, norpiguisone, and lunularin have been isolated from Porella platyphylloidea (L.) Pfeiff., Conocephalum conicum (L.) Dumort, and Lunularia cruciate (L.) Dumort. ex Lindb.
Medicinal plants are still being used in domestic households for many infectious diseases. For instance, paste of Rheum emodi Wall. is used to cure abscesses and boils in many parts of the North-Western Himalayas, particularly in Kashmir Valley; a fermented product of Viola odorata L. is used to treat respiratory tract infections; and roots of Juglans regia L. are used to treat gum infections [19][111]. Despite the availability of modern antibiotics, many parts of the Himalayan region, particularly the tribal population, still practice and prefer herbal medicine over modern antibiotics. Although many plant species of Himalayan medicinal plants have been investigated for their antimicrobial activities, given the medicinal plant diversity of the Himalayas, extensive research is needed to explore the untapped reserve of phytochemicals produced by the medicinal plants. The phytochemicals could act as novel antimicrobials, antibiotic potentiators, or resistance breakers.

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