Alkaloids: The Potential of Their Antimicrobial Activities of Medicinal Plants

Abstract

Given the potential adverse effects of chemical drugs, utilizing natural products with diverse therapeutic and antimicrobial compounds is advisable. Countries can use indigenous flora from their regions in vegetation for medicinal purposes. Several nations exhibit distinctive indigenous flora owing to their geographic positioning and climatic conditions. These plants have been the subject of our research, which has explored their antimicrobial properties against fungi, parasites, bacteria, and viruses. Studies have investigated the therapeutic and antimicrobial effects of plants and their bioactive compounds, such as alkaloids, flavonoids, and terpenoids. Among them are alkaloids, a diverse class of naturally occurring chemicals, such as tropanes, terpenoids, and steroids. Some of these medicinal plants have been found to possess antioxidant and anti-inflammatory properties in addition to their antimicrobial effects. This chapter explores the antimicrobial potential of alkaloids found in medicinal plants.

1. Introduction

Researchers are discovering infectious diseases are a major threat to world health [1, 2]. For millennia, medicinal plants have yielded an abundance of therapeutic compounds, which have been incorporated into traditional pharmacological practices across the globe [3, 4]. Since the dawn of time, people have known that plants have healing properties, making botanic medicine one of the first forms of therapy [5, 6, 7]. Antibacterial medications have traditionally been derived from natural materials. This avenue of inquiry declined in the 1980s as scientists shifted their focus to synthetic compound libraries because of their greater flexibility [8]. Antibiotic and antifungal medication discovery are crucial in the face of the rise of multidrug-resistant (MDR) fungi and bacteria [9]. The emergence of multidrug-resistant organisms is a significant worldwide health concern [10]. The incorrect use of antibiotics in human and animal health care is largely responsible for the rise of MDR strains. Consequently, the search for alternative, nonantibiotic-dependent solutions to this critical issue has become an urgent and imperative challenge [11]. In particular, each plant produces small quantities of secondary metabolites—tiny compounds like terpenoids, polyphenols, phenolics, alkaloids, essential oils, etc. [12]. The discovery of novel pharmacological compounds that can treat serious ailments has greatly benefited from research into medicinal plants [13]. Some plants, such as mustard, ginger, basil, garlic, cinnamon, sage, curry, and many other crude extracts, for instance, have antibacterial activity against many different forms of bacteria, including gram-positive and gram-negative [14]. Medicinal plants include phytochemicals, often responsible for their biological activity, commonly found in these plant sources [1]. Secondary metabolites found in plants include active chemical molecules with potential therapeutic applications for various diseases [15]. Isolated secondary metabolites in plants are thought to account for fewer than 10% of the total. Metabolites are commonly employed to safeguard against insects, herbivores, and microbes. The diverse range of aromatic substances and their oxygen-substituted derivatives plants synthesize accounts for the extensive variety observed [16]. Recently, drug resistance has emerged as a major issue in healthcare; the rate at which drug-resistant diseases are increasing is far higher than the rate at which new medications are being tested and authorized for human use. Thus, it is crucial to create new antimicrobial drugs [17, 18, 19].

Infectious illnesses caused by microorganisms significantly contribute to human suffering and death. About 60% of the biomass on Earth is thought to be composed of microbial species. This, together with their tremendous genetic, metabolic, and physiological variables, renders them a danger to the well-being and progress of human communities everywhere [20]. Hence, nature is the source of a significant proportion of the drugs currently used, derived from microorganisms, flora, or fauna. Identifying and synthesizing novel compounds possessing pharmacological properties depends on the natural environment’s biodiversity [12, 21]. Many plant components are available without a prescription from herbal distributors and natural-food stores, and self-administration of these drugs is common even though their purity is often questionable [22]. Chemical analysis of medicinal plants has uncovered various bioactive chemicals, including saponins, tannins, and alkaloids [1, 23]. Also, flavonoids, terpenoids, and alkaloids are the primary constituents of phytochemicals in the plant kingdom [24]. The pharmacologically active compounds encompass a variety of alkaloids that can be categorized into several classes, such as piperidines, pyrrolizidines, quinolizidines, imidazoles, tropanes, pyrrolidines, indoles, isoquinolines, and purines [15]. They belong to a vast group of naturally occurring chemical compounds that include at least one nitrogen atom (particularly in the form of an amino or amido group). The nitrogen atoms often form a ring shape [25]. Alkaloids are plant-derived bioactive compounds typically exhibiting alkaline properties due to their nitrogen atoms [26].

With many plants still waiting to be discovered and examined for their phytochemical compositions, the future of therapeutic plants seems bright. Synthetic medicine design and development have benefited from learning about medicinal plants [1]. Thus, alkaloids are the subject of intensive study because they may constitute a novel class of naturally occurring antibiotics with a broad antibacterial range, few side effects, and a low propensity to result in drug resistance. The present chapter centers on investigating the antimicrobial potential of alkaloids obtained from medicinal plants against human pathogenic microorganisms, specifically emphasizing multi-drug-resistant clinical strains. The chapter elucidates the mechanism of action of these alkaloids when available and underscores their concentrations and usage.

2. Plant products as an antimicrobial agent

Pathogenic bacteria create dangerous and potentially fatal infectious diseases that affect humans [27, 28]. On the other hand, antibiotic resistance is a significant issue in the twenty-first century, and infectious illnesses are still the second-greatest cause of mortality globally despite the success of antibiotic discoveries [1]. The growing incidence of antimicrobials-microbes resistance is causing growing alarm among scientists. The advent of drug-resistant bacteria has increased the difficulty and expense of creating newer antimicrobials from novel chemical compounds [15, 28]. Despite the approval of synthetic antimicrobial agents in numerous countries, using natural compounds derived from microbial, animal, or plant sources has garnered significant interest among researchers [29]. Numerous researchers are currently engaged in the investigation of plants to identify potential antimicrobial agents [15]. The quest for compounds possessing antimicrobial properties is common, and scholars have shown interest in medicinal plants due to their widespread use in traditional medicine as a treatment for various infectious ailments [30]. Hence, the demand for and research into plant-based pharmaceuticals and nutritional aids has increased rapidly in recent years [31]. Studies conducted on plants utilized in traditional medicine have been performed in vitro within the realm of microbiology, with a particular focus on the proliferation of infectious bacteria [30]. Betoni et al. found that plant compounds can either act as antimicrobial agents that complement antibiotics or increase a pathogen’s susceptibility to an antibiotic that would have otherwise been ineffective [30].

Researchers from fields as diverse as ethnopharmacology, botany, microbiology, and natural products chemistry scour the planet in search of phytochemicals and “leads” that might be refined into effective antimicrobial drugs [31]. New medications can be developed by optimizing the structural makeup of phytochemicals present in plants [1]. Phytochemicals and other substances derived from plants have been used to treat a wide range of infectious diseases because they exhibit good antibacterial action against many human infections [29, 32]. However, it is widely established that several extracts and components of plants have antibacterial activity. Unfractionated extracts are typically used in these studies, despite their low in vitro antimicrobial activity. In vivo tests were rarely used to verify the results of these investigations [12]. Phytochemicals, which are bioactive organic chemical compounds, are present in medicinal plants [33, 34]. These compounds protect against chronic diseases, including those caused by metabolic or genetic disorders and infectious diseases. They are present in various foods made from plants, including cereals, veggies, and fruits [1]. There are several classes of phytochemicals, including carotenoids, alkaloids, phenolics, organosulfur compounds, and nitrogen-containing compounds [5].

3. Alkaloids

Alkaloids are naturally occurring compounds sourced from various organisms, including plants (which comprise approximately 300 plant families), bacteria, fungi, and animals [12]. The compounds and biomolecules exhibit significant diversity, yet all these chemicals are byproducts of the amino acid biosynthesis process or the transamination reaction [35]. Alkaloids are predominantly solid compounds that are commonly found in higher plants. The aforementioned botanical families, namely Leguminoceae, Papaveraceae, Solanaceae, Ranunculaceae, Annonaceae, Amaryllidaceae, Liliaceae, Apocynaceae, Boraginaceae, Loganiaceae, Magnoliaceae, Berberidaceae, Piperaceae, Gnetaceae, Rutaceae, Lauraceae, Menispermaceae, and Rubiaceae, are known to exhibit a high prevalence of the subject matter [36]. Certain plant species employ naturally occurring insecticides or pesticides to protect themselves against the harmful effects of select insect species. The synthesis of vegetal alkaloids primarily occurs in herbaceous and vascular plants [12]. The Arabic word al-qali designates the source of soda. German scientist Carl F. W. Meissner developed the term “alkaloid” in 1819 to describe this compound [36]. One of the biggest groups of secondary metabolites in plants, alkaloids are present in some economically relevant plant families [37]. As mentioned, they are present in various kingdoms. However, their distribution is restricted within each domain [8]. Alkaloids are classified into multiple categories. The categorization is founded upon the compounds’ heterocyclic ring structure and biosynthetic forerunners. The abovementioned compounds comprise indoles, pyrrolizidines, quinolizidines, pyrrolidines, piperidines, tropanes, isoquinoline, purines, and imidazoles [15]. The amino acids nicotinic acid, L-histidine, L-ornithine, L-tryptophan, L-lysine, L-tyrosine, acetate, L-phenylalanine, anthranilic acid, and L-phenylalanine are all precursors to the alkaloid phenylpropanoid [35]. Alkaloids also exhibit various pharmacological and biological properties and may be found in many herbal treatments [38]. Alkaloids have been the fundamental framework for advancing multiple antibiotics showing a broad activity spectrum [16]. Nicotine, caffeine, and cocaine are just a few examples of alkaloids incorporated into popular culture as drugs used for entertainment or abuse. Certain alkaloids have been identified as possessing high toxicity levels, resulting in numerous instances of human poisoning [16].

Alkaloids have a wide array of pharmacological activities, including antibacterial activity [12]. Most alkaloids exert their effects via efflux pump inhibitor (EPI) activity, which is considered a potential mechanism of antibacterial action [29]. In addition to their use as stimulant medications, alkaloids may be found in many of the foods and drinks we consume regularly. They have shown several pharmacological effects, including those of local anesthetic, anticancer, analgesic, pain-relieving, antifungal, anti-inflammatory, neuropharmacological, and antimicrobial, [25], antimalarial action, oxytocic and vasoconstrictor activity (ergometrine), activity against the central nervous system (brucine), and activity against the cholinergic system (atropine) [16]. Alkaloids, which derive their name from their resemblance to alkalis, can undergo salt formation upon reaction with acids, similar to inorganic alkalis. The nitrogen atoms exhibit basic properties in acid-base responses [25]. Alkaloids are characterized by a nitrogen atom that accepts protons and multiple amine hydrogens that donate protons. Hence, the biological activity of biomolecules is primarily attributed to their ability to establish hydrogen bonds with other biomolecules such as enzymes, receptors, and proteins [12, 24]. Thus, alkaloids can be used for a variety of pharmacological purposes [24]. Several antibiotics have been developed from alkaloids: the quinolones were discovered by accident during the production of quinine; the structure of metronidazole was altered from that of azomycin; and the quinoline scaffold was utilized to create bedaquiline [8]. Alkaloids can also be found in other medications like linezolid and trimethoprim scaffolding. Academic institutions, private companies, and public-private partnerships continue studying alkaloids to create effective antibacterial drugs [8].

A straightforward quantitative approach for identifying alkaloids in plants was developed by Li et al. [39]. Using tetrahydrofurfuryl methacrylate as the monomer, in situ radical polymerization was used to construct a polymer-based chromatographic monolithic column. Based on the results of the technique validation, the accuracy of the spiking recovery measures is between 98.89 and 102.06%. These findings demonstrate the constructed monolithic column’s viability for avoiding the lengthy analysis time required by conventionally packed C18 columns in quantitatively analyzing alkaloids from actual medicinal and culinary plant foods [39]. Alkaloids are used internally to improve health, physical performance, and the immune system. These entities are common in daily dietary intake, drinks, and supplementary products. Several compounds present in plants exhibit advantageous characteristics. Compounds such as caffeine, guaranine, and mateine, found in various plants, including coffee, have been observed to possess anti-inflammatory, antioxidant, and stimulatory properties. Additionally, cocoa contains theobromine and paraxanthine, which act as antioxidants. Ginger, conversely, contains gingerol and shogaols, which are phenolic alkenones that possess antioxidant, anti-inflammatory, antimicrobial, and antitumoral properties [37]. However, we provide a brief overview of the class of alkaloids concerning antimicrobial activity.

3.1 Alkaloids classification

At present, the number of identified alkaloids exceeds 18,000 [15]. Natural antibacterial alkaloids have been the subject of research since the 1940s, although most of the earliest studies did not go far enough to determine minimum inhibitory concentrations (MICs). Despite this class’s large number of chemicals, only a fraction of their biosynthesis routes have been determined [40]. The chemical makeup or inherent biological source of these entities determines their classification [16]. Chemical structure and characteristics are used to divide alkaloids into several classes. The feasibility of classifying alkaloids based on their natural origin arises because certain alkaloids are limited to specific sources [16]. The chemical structure or biological origin of alkaloids allows for two broad categories:

1. The initial category comprises three types: protoalkaloids, or biological amines, nonheterocyclic or unconventional alkaloids. These alkaloids contain nitrogen in their side chains. The following category includes the heterocyclic or conventional alkaloids, also known as true alkaloids, which possess nitrogen within the heterocycle, and pseudoalkaloids [36]. The basic carbon skeleton of pseudoalkaloids is not directly formed from amino acids. Still, it is connected to amino acid processes and is derived via an amination or transamination process from amino acid precursors or postcursors. Common pseudoalkaloids include capsaicin, caffeine, and ephedrine [36].

2. The second division may be subsequently classified into 14 subgroups based on the ring shape due to its deep structural complexity [16, 24].

As mentioned above, there are primarily three classes of alkaloids [36]:

3.1.1 Protoalkaloids

Alkaloids having a closed ring structure are protoalkaloids; they are chemically perfect but have a straightforward molecular structure. Among the alkaloids, they are in the minority [35]. The most notable examples of these alkaloids include yohimbine, mescaline, and hordenine (a phenethylamine) (Figure 1). Hordenine, a Tyr-derived phenylethylamine alkaloid, was initially discovered in Hordeum vulgare (barley) [41]. They are prescribed for various conditions, from mental illness to chronic pain to neuralgia. The nitrogen atom in these alkaloids comes from a source other than the heterocyclic ring structure; instead, it is generated from an amino acid. Typically, L-tryptophan and L-tyrosine are the precursors to these alkaloids. Simple alkaloids make form the framework of this minor class [36]. Protoalkaloids are compounds where the heterocyclic bond does not include the N atom from an amino acid. One type of alkaloid consists of compounds derived from the amino acids L-tryptophan and L-tyrosine [35].

Figure 1.

Some examples of protoalkaloids.

3.1.2 True alkaloids

These alkaloids and their precursor amino acids both have nitrogen in a heterocyclic ring. These entities exhibit high reactivity and possess significant biological efficacy [36]. These compounds can dissolve in water and form salts soluble in water. Additionally, many of these compounds exhibit a crystalline structure and can undergo conjugation with acids to form salts. Most authentic alkaloids are characterized by their solid state and bitter flavor, except nicotine, a brown liquid. Common true alkaloids include cocaine, morphine, and quinine [36]. Morphine, an alkaloid generated from tyrosine, has a nitrogen-containing heterocyclic ring and is used as a painkiller. It exhibits potent analgesic effects and is widely used as a painkiller in clinical settings [42]. Not all alkaloids show significant biological efficacy; some have no known pharmacological activity [43].

These subgroups have unique properties and uses, making them essential modern medicine and research components. Understanding the classification of alkaloids is an important step in understanding their potential therapeutic applications. For example, various pharmacological effects are associated with indole alkaloids found in plants, many of which are thought to be attributable to the indole nucleus [44]. Common plant families proven to contain indole alkaloids include Loganiaceae, Rubiaceae, Apocynaceae, and Nyssaceae. Preclinical and clinical research has shown that several of the discovered indole alkaloid compounds are particularly effective [44]. According to their antimicrobial activity, the most critical phytocompounds across all alkaloid chemical groups are shown in Table 1.

Types of alkaloids	Formula	Plant family	Targeted microorganism	Concentrations range (μg/mL)	Reference
Indole alkaloids
Brassicaceous indoles	C13H9N3O2S	Brassicaceae
Caulilexin A	C10H9NOS2	Brassicaceae	Sclerotinia sclerotiorum, Leptosphaeria maculans, Rhizoctonia solani	5 × 10^−4 M	[45]
Camalexin (3-thiazol-2′-yl-indole)	C11H8N2S	Brassicaceae	Alternaria brassicae	80 μg/mL	[46]
β-Carbolines	C11H8N2
Borrerine	C16H20N2	Rubiaceae	Staphylococcus aureus, Vibrio cholerae	50 and 6 μg/mL, respectively	[47]
Borreverine	C32H40N4	Rubiaceae	S. aureus, V. cholerae		[47]
Canthin-6-one (canthinone)	C14H8N2O	Simaroubaceae	S. aureus, Mycobacterium sp.	8–32 μg/mL	[48]
Rhetsinine	C19H17N3O2	Rutaceae	Xanthomonas oryxae pv oryzae, Xanthomonas oryxae pv oryzicola	1 and 4.5 μg/mL	[49]
Carbazoles	C12H9N
Glycozolidol	C14H13NO2	Nitrariaceae and Rutaceae	Proteus vulgaris, Bacillus firmis, S. lutea, S. aureus, Agrobacterium tumefaciens	200 μg/mL/well	[50]
Benzoisofuranone	C8H6O2	Rutaceae	S. aureus, B. subtilis, Escherichia coli, P. vulgaris, Aspergillus niger, Candida albicans	3.13–100 μg/mL	[51]
Harmane	C12H10N2	Nitrariaceae	V. anguillarum	3.1 μg/mL	[52]
			Cryptococcus neoformans, A. niger, Cryptococcus gattii, C. albicans	Very weak inhibited	[53]
Koenigine	C19H19NO3	Nitrariaceae and Rutaceae	Candida sp.	MIC90: 12.5–100 μg/mL	[54]
3,3′-[Oxybis(methylene)]bis(9-methoxy-9H-carbazole)	C28H24N2O3	Nitrariaceae and Rutaceae	P. vulgaris and C. albicans	6.2 and 25 μg/mL, respectively	[51]
Monoterpenoid indole alkaloids
Scholarisine	C19H18N2O2	Apocynaceae	Gibberella pulicaris and Cercospora nicotianae	MIC: 1.37–1.91 μM	[55]
Kopsiflorine	C23H28N2O5	Apocynaceae	S. aureus	IZ: 9.7 mm	[56]
Erchinines A and B	—	Apocynaceae	B. subtilis, Trichophyton rubrum	0.78 and 0.78, 12.5 and 6.25, respectively	[57]
Melokhanine A	C19H26N2O3	Apocynaceae	Pseudomonas aeruginosa, Enterococcus faecalis	2–5 μM	[58]
Ibogaine	C20H26N2O	Apocynaceae	E. coli, B. subtilis, A. flavus, A. niger, Rhizoctonia phaseoli, K. pneumoniae, S. aureus, S. pneumoniae, A. flavus, C. albicans, and R. phaseoli	50–60 μg/mL	[59]
Vobasine	C21H24N2O3	Apocynaceae	A. niger and A. flavus	50–60 μg/mL	[59]
Voacamine	C43H52N4O5	Apocynaceae	R. phaseoli, P. chrysogenum, and C. albicans	50–60 μg/mL	[59]
Cadambine	C27H32N2O10	Rubiaceae	Weakly against: Staphylococcus epidermidis, S. aureus, B. cereus, B. subtilis, and C. albicans	3.3–164 μg/mL	[60]
Strictosidine	C27H34N2O9	Rubiaceae	K. pneumoniae, Providencia smaitii, and E. coli	12.5, 25, and 50 μg/mL, respectively	[61]
Tubotaiwine	C20H24N2O2		Mycobacterium tuberculosis	100 μg/mL	[62]
Diterpene alkaloids	C24H39NO4	Ranunculaceae
Vilmorrianone, panicutine, 8-acetylheterophyllisine	C23H29NO4	Ranunculaceae	Allescheria boydii, A. niger, E. floccosum, Pleurotus ostreatus	–	[63]
Miscellaneous
Tryptanthrin	C15H8N2O2		E. floccosum, T. mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, M. gypseum, and Microsporum canis	3.1–6.3 μg/mL	[64]
			C. neoformans, and Cryptococcus deuterogattii	MIC/MFC: 2/ > 64 and 8/32 μg/mL	[65]
Dehydroevodiamine	C19H15N3O	Rutaceae	X. oryxae pv oryzae	1.4 μg/mL	[49]
Piperidine Alkaloids
Piperlongumine	C17H19NO5	Piperaceae	C. albicans, S. aureus and P. aeruginosa	MIC: 3.9 μg/mL	[66]
Piperine	C17H19NO3	Piperaceae	C. albicans, R. solani, Fusarium gramineum, Alternaria tenuissima, Gloeosporium theae-sinensis, Phytophthora capsici, and Phomopsis adianticola	100 μg/mL	[66]
Quinolizidine
Quinolizidine	C9H17N	Nymphaeaceae, Fabaceae	E. faecalis, Enterococcus faecium, S. aureus, and Methicillin-resistant Staphylococcus aureus (MRSA)	2–16 μg/mL	[67]
Phenanthroindolizidine		Lauraceae, Moraceae, Asclepiadaceae
7-Demethoxytylophorine	C23H25NO3	Apocynaceae	Penicillium italicum, Penicillium digitatum	MIC/MFC: 1.5/6.2 and 1.5/12.5 μg/mL, respectively	[68, 69]
Tylophorinine	C23H25NO4	Apocynaceae	C. albicans, Candida krusei, Candida glabrata, and A. fumigatus	0.6–5 μg/mL	[68]
Tylophorinidine	C22H23NO4	Apocynaceae	C. albicans, Candida krusei, Candida glabrata, and A. fumigatus	2–8 μg/mL	[68]
Securinega alkaloids
viroallosecurinine	C13H15NO2	Phyllanthaceae	P. aeruginosa and S. aureus	MIC: 0.4 μg/mL	[70]
Securinine, Allosecurinine	C13H15NO2	Phyllanthaceae	P. aeruginosa, S. aureus, and M. smegmatis	Weak activity	[70]
norsecurinine	C12H13NO2	Phyllanthaceae	filamentous fungi	Inhibited at Low concentrations	[71]
Miscellaneous
Dihydrodioscorine	C13H21NO2	Dioscoreaceae	Sclerotium rolfsii, C. lunata, F. moniliforme, Botryodiplodia theobromae, and Macrophomina phaseolina	Inhibited the mycelial growth	[72]
Pandamarilactone-1	C18H23NO4	Dioscoreaceae	E. coli, P. aeruginosa, and S. aureus	Weak activity	[73]
Haloxyline B	—	Chenopodiaceae	M. tuberculosis H37Rv	50 μg/mL	[74]
Quinoline Alkaloids
Simple Quinolines
4-Methylquinoline	C10H9N	—	S. aureus	MIC/MBC values of 12.2/50 μg/mL	[75]
4-methoxy-2-phenylquinoline	C16H13NO	Rutaceae	M. tuberculosis H37Rv	16 μg/mL	[75]
Dictamine	C12H9NO2	Rutaceae	Micrococcus luteus (TISTR 884) and B. cereus (TISTR 688)	26 and 64 μg/mL, respectively	[76]
γ-Fagarine	C13H11NO3	Rutaceae	broad-spectrum antibacterial	Moderate activity	[77]
Robustine	C12H9NO3	Rutaceae	broad-spectrum antibacterial	Moderate activity	[77]
Benzylisoquinolines
Reticuline	C19H23NO4
Fuyuziphine	—	Papaveraceae	Alternaria brassicicola, A. solani, Alternaria melongenae, C. maculans, Erysiphe cichoracearum, and Helminthosporium pennisetti	500 ppm	[78]
Bisbenzylisoquinolines
Tetrandrine	C38H42N2O6	Menispermaceae	S. aureus and MRSA	weakly bactericidal	[79]
Tiliacorinine	C36H36N2O5	Menispermaceae	M. tuberculosis	6.2 μg/mL	[80]
2′-nortiliacorinine	C35H34N2O5	Menispermaceae	M. tuberculosis	3.1 μg/mL	[80]
Tiliacorine	C36H36N2O5	Menispermaceae	M. tuberculosis and A. tenuissima	3.1 and 100 μg/mL, respectively	[80, 81]
Aporphines
Aporphine	C17H17N	Illiciaceae, Trimeniaceae	bacteria and fungus in plants	suppressed a wide variety of bacteria and fungus	[82]
Liriodenine	C17H9NO3	Illiciaceae, Trimeniaceae	bacteria and fungus in plants	suppressed a wide variety of bacteria and fungus	[82]
Anonaine	C17H15NO2	Magnoliaceae, Annonaceae	B. cereus, E. coli, S. aureus, and S. epidermidis	diameters of 20, 8, 14, and 12 mm, respectively	[83]
Lysicamine	C18H13NO3	Annonaceae	L. monocytogenes, Methicillin-resistant Staphylococcus aureus (MSSA), S. pneumoniae, Actinobacillus sp., and K. pneumoniae	1.4–20 μg/mL	[84]
O-methylmoschatoline	C19H15NO4	Annonaceae	B. subtilis, E. coli, and Salmonella typhi	64 μg/mL	[82]
Artabotrine	C20H23NO4	Annonaceae	K. pneumoniae	MIC/MBC: 2.5/2.5 μg/mL	[84]
Azaoxoaporphine sampangine	C15H8N2O	Annonaceae	C. albicans, C. glabrata, C. kruseii, A. fumigatus, and C. neoformans	3.1, 3.1, 6.2, 6.2, and 0.05 μg/mL, respectively	[85]
Lanuginosine	C18H11NO4	Annonaceae	B. cereus, S. aureus, E. coli, K. pneumoniae, and P. aeruginosa	IZ: 12, 14, 10, 14, and 12 mm, respectively	[86]
Nordicentrine	C19H19NO4	Menispermaceae	M. tuberculosis	12.5 μg/mL	[87]
Dicentrinone	C19H13NO5	Menispermaceae	M. tuberculosis	Moderate antimycobacterial	[88]
Oxoaporphine thailandine	C39H62O14	Menispermaceae	S. pneumoniae, S. aureus, E. faecalis, and M. tuberculosis	30, 30, 60, and 6.2 μg/mL, respectively	[89]
Isoboldine	C19H21NO4	Ranunculaceae	A. baumanii, B. subtilis, C. albicans, P. aeruginosa, E. coli, P. mirabilis, K. pneumoniae, and S. aureus	Moderate activity	[90]
Roemerine	C18H17NO2	Lauraceae	MRSA, A. fumigatus, C. albicans, C. glabrata, C. krusei, Candida tropicalis, Candida parapsilosis, and S. aureus	10 μg/mL for C. albicans	[91, 92]
Magnoflorine	C20H24NO4+	Menispermaceae	C. albicans, C. parapsilosis var. parapsilosis, T. rubrum, and T. mentagrophytes	Moderate activity	[93]
Protopines
Protopine	C20H19NO5	Papaveraceae	C. albicans	4 μg/mL	[90]
Allocryptopine	C21H23NO5	Papaveraceae	P. aeruginosa, S. aureus, E. coli, and S. agalactiae	Weak activity	[94]
Protoberberines
Pendulamine A	—	Annonaceae	B. subtilis, P. aeruginosa, S. aureus, Corynebacterium hoffmanii, K. pneumoniae, S. typhi, Micrococcus lysodickycus, and S. paratyphi A	0.02–2 μg/mL	[95]
Pendulamine B	—	Annonaceae	Corynebacterium hoffmanii, S. faecalis, S. aureus, S. typhi, S. viridans, M. lysodickycus, P. aeruginosa, K. pneumoniae, and S. paratyphi A	0.02–2 μg/mL	[95]
Spirobenzylisoquinolines
Parfumine	C20H19NO5	Papaveraceae	A. baumanii, B. subtilis, K. pneumoniae, E. coli, P. aeruginosa, P. mirabilis, and S. aureus	Moderate activity	[90]
Fumarophycine	C22H23NO6	Papaveraceae	A. baumanii, B. subtilis, K. pneumoniae, E. coli, P. aeruginosa, P. mirabilis, and S. aureus	Moderate activity	[90]
Fumariline	C20H17NO5	Papaveraceae	A. baumanii, B. subtilis, K. pneumoniae, E. coli, P. aeruginosa, P. mirabilis, and S. aureus	Moderate activity	[90]
Benzophenanthridines
Stylopine or sanguinarine	C20H14NO4+	Papaveraceae	A. baumanii, B. subtilis, K. pneumoniae, E. coli, P. aeruginosa, P. mirabilis, and S. aureus	Moderate activity	[90]
Dihydrosanguinarine	C20H15NO4	Papaveraceae	S. mutans, S. aureus, P. aeruginosa, E. coli, and S. agalactiae	32, 31.3, 250, 62.5, 15.6 μg/mL	[94]
6-Methoxydihydrosanguinarine	C21H17NO5	Papaveraceae	S. aureus and MRSA	IZ: 17 mm	[96]
			E. faecalis and S. aureus	MIC/MBC: 5/10, 2.5/5 μg/mL	[97]
8-Hydroxydihydrosanguinarine		Papaveraceae	MRSA	MIC range: 0.4 to 7.8 μg/mL, and MBC range: 1.9 to 31.2 μg/mL	[81]
Norsanguinarine	C19H11NO4	Papaveraceae	A. baumanii, B. subtilis, K. pneumoniae, E. coli, P. aeruginosa, P. mirabilis, and S. aureus	Moderate activity	[90]
Allocryptopine	C21H23NO5	Papaveraceae	S. epidermidis, S. aureus, S. pyogenes, B. subtilis, K. pneumoniae, and E. coli	6.2/12.5, 12.5/50, 12.5/50, 25/50, 12.5/25, 25/25 μg/mL, respectively	[98]
8-Hydroxydihydrochelerythrine	C21H19NO5	Papaveraceae	MRSA	MIC: 0.9–15.6 μg/mL, MBC: 7.8–62.5 μg/mL	[99]
Dihydrochelerythrine	C21H19NO4	Papaveraceae	MRSA, E. coli	8–128 5 μg/mL	[77]
Chelerythrine	C21H18NO4	Papaveraceae	C. albicans, S. cerevisae, and C. neoformans	MIC/MBC: 3.1/3.1, 6.2/6.2, and 3.1/6.2 μg/mL, respectively	[98]
Corynoline	C21H21NO5	Papaveraceae	Cladosporium herbarum	3 μg/spot	[100]
Acetylcorynoline	—	Papaveraceae	C. herbarum	3 μg/spot	[100]
Norchelerythrine	C20H15NO4	Rutaceae	M. tuberculosis	25 μg/mL	[101]
Avicine	C20H14NO4+	Rutaceae	S. epidermidis, S. aureus, S. pyogenes, B. subtilis, K. pneumoniae, and E. coli	3.1/12.5, 1.5/25, 1.5/12.5, 1.5/6.2, and 6.2/12.5 μg/mL, respectively	[98]
Rhoifoline B	C21H17NO5	Rutaceae	S. aureus, S. epidermidis, E. coli, E. cloacae, K. pneumoniae, P. aeruginosa, and S. dysenteriae	Moderate activity	[102]
Nitidine	C21H18NO4+	Rutaceae	M. luteus, S. aureus, and M. smegmatis	Weak activity	[103]
Protoberberines
Berberine	C20H18NO4+	Berberidaceae	K. pneumonia and A. baumanii	8 μg/mL	[90]
Palmatine	C21H24NO4+	Berberidaceae, Papaveraceae, Ranunculaceae, and Menispermaceae	A. baumanii, E. coli, P. mirabilis, P. aeruginosa, K. pneumoniae, S. aureus, and B. subtilis	Moderate activity	[90]
Phthalides
Bicuculline	C20H17NO6	Fumariaceae	A. brassicae, F. udum, and Curvularia lanata	200 ppm	[90]
Hasubanans
Glabradine	C19H19NO7	Menispermaceae	S. aureus and S. mutans	50 μg/mL	[104]
Amaryllidaceae Alkaloids		Amaryllidoideae
Crinamine	C17H19NO4	Amaryllidoideae	Some bacteria	—	[105]
Lycorine	C16H17NO4	Amaryllidoideae	C. glabrata, Candida dubium, C. albicans, Lodderomyces elongisporus, and S. cerevisae	512, 39, 32, 64, and 97.3 μg/mL	[78]
			Alternaria oleracea, C. gloeosporioides, F. graminearum, Colletotrichum ophiopogonis, and Pleospora lycopersici	100 μg/mL	[106]
Lycoricidine		Amaryllidoideae		IZ: 12 mm	[78]
Narciclasine	C14H13NO7	Amaryllidoideae	Corynebacterium fascians and C. neoformans	Highly growth inhibition	[107]
Tazettine	C18H21NO5	Amaryllidoideae	L. elongisporus and C. dubliniensis	Weak activity	[108]
Miscellaneous
Quinolinones
Antidesmone	C19H29NO3	Euphorbiaceae	Carbendazim-sensitive strains of S. sclerotiorum, and Carbendazim-resistant strains of S. sclerotiorum Botryosphaeria dothidea, Pestalotipsis guepinii, Colletotrichum musae, Colletotrichum orbiculare, Pestalotiopsis longiseta Phylophthora nicotianae	50 μg/mL	[109]
Waltherione C	C22H21NO3	Malvaceae	B. dothidea, Colletotrichum orbiculare, Colletotrichum musae, Pestalotiopsis longiseta, Pestalotipsis guepinii, Phylophthora nicotianae, carbendazim-sensitive strains of S. sclerotiorum, and carbendazim-resistant strains of S. sclerotiorum	50 μg/mL	[109]
Evocarpine	C23H33NO	Rutaceae	MRSA and S. aureus	8 μg/mL	[110]
Acridanones
1-hydroxy-3,4-dimethoxy-10-methylacridan-9-one	C16H15NO4	Rutaceae	E. coli	Growth inhibition	[51]
Phenanthrene Alkaloids
Aristolochic acid	C17H11NO7	Aristolochiaceae	Moraxella catarrhalis	MIC and MBC: 25/50 μg/mL	[111]
1-N-monomethylcarbamate-argentinine-3-O-β-d-glucoside	—	Menispermaceae	MRSA	500 μg/disk, IZ: 8 mm	[112]
Pyrrolidines and Imidazole Alkaloids		Piperaceae
Pyrrolidines		Piperaceae
Brachyamide B	C20H25NO3	Piperaceae	C. albicans	IC50: 41.8 μg/mL	[113]
Pandanus lactones			C. neoformans	IC50: 7.1 μg/mL	[114]
Pandamarilactonine A	C18H23NO4	Pandanaceae	E. coli, P. aeruginosa, and S. aureus	Moderate activity	[73]
Diterpene Alkaloids		Ranunculaceae
8-acetylheterophyllisine	C24H35NO5	Ranunculaceae	Pleurotus ostreatus, Allescheria boydii, A. niger, and E. floccosum	Growth inhibition	[63]
Vilmorrianone	C23H27NO5	Ranunculaceae	Pleurotus ostreatus, Allescheria boydii, A. niger, and E. floccosum	Growth inhibition	[63]
Panicutine	C23H29NO4	Ranunculaceae	Pleurotus ostreatus, Allescheria boydii, A. niger, and E. floccosum	Growth inhibition	[63]
Steroidal Alkaloids
N-formylconessimine	—	Apocynaceae	MSSA	32 μg/mL	[115]
Conimine	C22H36N2	Apocynaceae	MRSA	128 μg/mL	[115]
Isoconkuressine	—	Apocynaceae	MSSA and MRSA	Growth inhibition	[115]

Table 1.

Classification of alkaloids in plants family based on their antimicrobial activity.

IZ: inhibition zone; and MIC: minimum inhibitory concentration.

Monoterpenoid indole alkaloids are a class of widely recognized alkaloids that are derived from tryptamine and secologanin. Numerous alkaloids exhibit intricate structures and significant biological properties, rendering them intriguing. Various species belonging to the Apocynaceae family, including Tabernanthe iboga, Voacanga africana, and multiple Tabernaemontana species, synthesize alkaloids, including the ibogan type [116]. Antibiotic and well-known alkaloid tryptanthrin (TRYP) (indolo[2,1-b]quinazolin-6,12-dione) is found in Candida lypolica, higher plants, and numerous marine microbes [117]. Various biological and pharmacological qualities are related to the several structural scaffolds, and a wide variety of functional group modifications is found in the broad class of plant-specific metabolites known as benzylisoquinoline alkaloids. N-Methylation is a widely used modification technique that forms intermediates and final products in the tertiary and quaternary metabolic pathways [118].

3.2 Some selected alkaloids with antimicrobial activity

Various alkaloids found in nature have been shown to have antimicrobial effects against a wide range of diseases [15]. Some selected alkaloids with potent antimicrobial activity include berberine, quinine, and vincristine. The potential for these particular alkaloids’ antibacterial action to expand therapy choices for infectious disorders caused by drug-resistant microbes or those not responding to conventional therapies has been widely discussed [16]. Hence, this review focuses on alkaloids with antibacterial activity against MDR microorganisms. Also, this article describes the most influential alkaloids with potent antibacterial properties. Here are some selected examples of these compounds:

3.2.1 Berberine

The natural isoquinoline alkaloid berberine has been shown to have minimal toxicity [119]. Berberine, derived from Berberis spp., is a prominent quaternary ammonium salt of protoberberines. It exhibits various antimicrobial properties, particularly against Gram-negative bacteria [24]. Berberis vulgaris, Coptis chinensis, Hydrastis canadensis, Coptidis rhizoma, Xanthoriza simplicissima, Phellodendron amurense, and Chelidonium majus all contain it, among many others, making them useful as therapeutic herbs [119]. Berberine is an effective antibacterial agent that may one day replace conventional antibiotics and help combat the problems caused by antibiotic resistance. Methanol extract of Pancratium illyricum L. bulbs yielded the isoquinoline alkaloid ungeremine. Its antimicrobial qualities have been well-praised. As mentioned earlier, the compound can induce a significant augmentation in DNA cleavage through its selective targeting and inhibition of bacterial topoisomerase IA [29]. Herpes, influenza, and respiratory syncytial viruses are susceptible to berberine’s antiviral actions [34, 119]. Berberine’s mechanism of action against V. cholerae and E. coli-induced diarrhea has been thoroughly investigated. The effects of E. coli and V. cholerae enterotoxins were found to be directly inhibited by berberine in vitro as early as 1982 [120]. Berberine’s antibacterial activity against S. aureus has been shown in in vitro investigations [121]. As reported in reference, berberine and CinA can undergo self-assembly, forming nanoparticles (NPs) that exhibit bacteriostatic properties against MRSA and potentially eliminate biofilms [40]. Cinnamaldehyde (CinA) is a principal constituent of the Cinnamomi cortex, a traditional spice that finds extensive usage in everyday routines [122].

The alkaloid berberine sulfate is harvested from the bark and roots of several plants. It exhibits antibacterial, antifungal, and antiprotozoal properties. Berberine sulfate disrupts fimbrial formation in Streptococcus pyogenes, impeding bacterial attachment to mucosal or epithelial surfaces [123]. On the other hand, L-Tyr is widely recognized as the biosynthesis precursor of berberine. 13 different enzymatic processes are involved in the production of berberine from L-Tyr. Notably, biochemical analysis has been performed on all of the enzymes in this pathway [24].

3.2.2 Caffeine

Numerous plant species derive caffeine (1,3,7-trimethyl xanthine) from methylated alkaloids. It is structurally related to uric acid [124]. However, recent studies have shown that caffeine also has antimicrobial properties, which has led to increased interest in its potential use as an alternative to traditional antibiotics. Understanding caffeine’s antimicrobial activity is crucial in developing new treatments for drug-resistant infections, making it an important area of research. Another study by Ibrahim et al. found that growth inhibition was most noticeable at concentrations of 0.50% and above against E. coli [124]. Also, caffeine concentrations in coffee extracts are high enough to concern human health, with 50% antibacterial activity against S. enterica [125].

3.2.3 Capsaicin (CAP)

The berries of virtually all peppers in the genus Capsicum contain capsaicin, also known as 8-methyl-N-vanillyl-6-nonenamide [12]. Peppers, especially chili peppers, are members of the Solanaceae plant family, responsible for their distinctive flavor [11]. Capsicum annuum powder is a commonly utilized seasoning in various culinary traditions across the globe. Apart from its gastronomic application, CAP is employed for analgesic purposes in different severe and persistent medical conditions [12]. Pepper fruits may contain capsaicin at a rate of up to 1% of their total weight. It is naturally produced in the epidermal cells of the placenta, which are located close to the seeds. The compound tends to accumulate in the form of “blisters” on the surface of the placenta. The molecule is a potent agonist of the transient receptor potential vanilloid ion-channel receptor 1 (TRPV1), eliciting its characteristic hot, burning sensation. However, the beneficial effects of capsaicin and the TRPV1 receptor cannot be attributed primarily to this interaction [11]. In an in vitro investigation [126], six capsaicin derivatives were developed, each possessing phenolic hydroxyl, a benzene ring, and amide structures. These derivatives were subsequently evaluated for their antibacterial properties against E. coli and S. aureus. Two powerful chemicals found in Capsicum species were shown to have antimicrobial capabilities, and Cichewicz and Thrope identified them. The experiment results showed that the plain and heated extracts displayed different levels of inhibition against Streptococcus pyogenes, B. subtilis, B. cereus, Clostridium tetani, and Clostridium sporogenes [127].

3.2.4 Colchicine

Colchicine has been around longer than most other pharmaceuticals [128]. The use of colchicine as a pharmacological agent in humans has been permitted by the Food and Drug Administration (FDA). It is a safe and productive anti-inflammatory medication derived from the Colchicum and Gloriosa plant species. Colchicine has been utilized in treating cardiovascular ailments due to its distinctive effectiveness as an anti-inflammatory agent [24]. The chemical origins of colchicine have been the subject of extensive research, facilitated by numerous feeding studies utilizing isotope-labeled substrates in Colchicum plants. Furthermore, a well-defined biosynthetic hypothesis has been established thanks to structural study of colchicine-related alkaloids isolated from several members of the Colchicaceae family [24]. The first biosynthetic studies on colchicine were performed by Leete in 1960 [129].

The medical application of colchicine in cancer chemotherapy is restricted due to its comparatively high toxicity, despite its potency as an anticancer agent. Nevertheless, colchicine is currently utilized in therapy [130]. Colchicine’s potential anticancer impact on hypo-pharyngeal carcinoma was studied. Colchicine dose-dependently suppressed hypo-pharyngeal human cell proliferation [128]. Colchicine inhibited adhesion, migration, and cell invasion via decreasing expression of MMP9, uPA, and FAK/SRC [128]. Researchers have shown that colchicine inhibits the reproduction of the Flaviviridae family of viruses by blocking microtubule polymerization. Researchers believe colchicine, a well-known anti-inflammatory medication, can cure COVID-19 by decreasing inflammation [131].

3.2.5 Piperine

Piperine has been extracted from various species of the Piperaceae botanical family [132], as shown chemically in Figure 2 [132]. Piperine is a major compound of black pepper (Piper nigrum) and long pepper (Piper longum), two species of the Piperaceae family. Studies suggest piperine exhibits bioavailability-enhancing properties for select nutritional substances [133]. The biting quality that is distinct from black pepper is attributed to piperine. Piperine exhibits numerous pharmacological properties and confers various health advantages, particularly for chronic ailments. These benefits include mitigation of anti-inflammatory effects, insulin resistance, amelioration of hepatic steatosis [134], anti-aging, antidiabetic, cardioprotective, antimicrobial, and anti-obesity [132]. When ciprofloxacin and a piperidine-type alkaloid from the plants. Together, P. longum and P. nigrum were able to inhibit the development of a mutant S. aureus and considerably reduce MIC values for S. aureus [135].

Figure 2.

Piperine and its structural isomers (adapted from Ul-Haq et al. [132]).

In the case of absorption, it is noteworthy that piperine exhibits no metabolic transformations upon absorption, as evidenced by its presence in both intestinal tissues and serosal fluid. This suggests that piperine remains unaltered throughout the absorption process [132].

3.2.6 Reserpine

Reserpine, an indole alkaloid extracted from the plant Rauwolfia serpentina, is well-known for its potent EPI action. The co-administration of reserpine has improved the antibiotic susceptibility of various bacterial species, such as Micrococcus spp., Streptococcus spp., and Staphylococcus spp. [29]. Combining reserpine with other commercially available antibiotics has been shown to improve the antibiofilm response and eradicate a sizable amount of bacterial biofilm in a urinary catheterization model, as reported by Parai et al. [136]. In another study, many acyl reserpine derivatives were made and tested for their antimycobacterial and antioxidant activities against Mycobacterium TB, strain H (37) Rv. This was done because reserpine is thought to have therapeutic benefits. According to the findings, 10 of 18 derivatives exhibited more significant suppression of antimycobacterial activity than reserpine [137]. On the other hand, reserpine inhibits AcrB. Acriflavine resistance protein B (AcrB) is an MDR efflux transporter that belongs to the Resistance-nodulation-division (RND) superfamily [138].

3.2.7 Tomatidine

Steroid alkaloid tomatidine is harvested from nightshade plants, including tomatoes, potatoes, and eggplant. As monotherapy or in combination with aminoglycosides, there is evidence that it is highly effective as an antibacterial agent against S. aureus [29]. Tomatoes and tomatidine, as found by Silva-Beltrán et al., have great promise as a source of several bioactive chemicals, antioxidants, and antibacterial agents [139]. Tomatidine exhibited bacteriostatic activity against small-colony variants linked to their impaired electron transport system. The electron transport inhibitor 4-hydroxy-2-heptylquinoline-N-oxide (HQNO) increased the sensitivity of typical S. aureus strains to tomatidine [140].

3.2.8 Conessine

Holarrhena antidysenterica, a member of the Apocynaceae family, has a long history of medical usage for treating dysentery, diarrhea, fever, and bacterial infections [141]. Conessine is a steroidal alkaloid. The therapeutic actions of H. antidysenterica barks are due to the presence of alkaloids, specifically the steroidal alkaloid conessine. There is preliminary evidence that this compound can kill gram-positive and gram-negative bacteria [141]. Based on the existing evidence, it can be inferred that the steroidal crude extract of H. antidysenterica and conessine exhibit properties of efflux pump inhibitors (EPIs). Recently, it has been reported that the steroidal extract and alkaloid conessine can augment the efficacy of antibiotics by impeding the AdeIJK efflux pump in A. baumannii [142].

Other alkaloid classes, namely indolizidine, pyrrole-imidazole alkaloid, quinoline, aaptamine, indole, isoquinoline, piperazine, polyamine, bisindole, quinolone, indole-quinoline, agelasine, aaptamine-indole, pyridoacridine, and bispyrrole have been reported to exhibit antibacterial activity [37].

4. Alkaloids derived from medicinal plants and their antimicrobial activities

The distribution of alkaloids within plant tissues is heterogeneous, as mentioned previously, with varying concentrations observed across plant parts such as roots, seeds, leaves, fruits, and bark. Distinct alkaloid types may exist in various parts of a single plant [12]. The alkaloids are the most abundant secondary metabolites in the Zanthoxylum genus, and they exhibit a wide variety of biological functions due to their structural diversity [143]. A study by Farouk et al. indicated that Eurycoma longifolia leaf extracts were tested for antibacterial efficacy against Pseudomonas aeruginosa and S. aureus bacteria. The extracts were prepared using various solvents, including acetone, ethanol, phosphate buffer, and methanol at 5–100 mg/mL concentrations. Several extracts inhibited bacterial growth, with the widths of the inhibition zones ranging from 7 to 25 mm [144]. In addition to causing serious side effects, treating fungal infections with antifungal drugs often leads to drug-resistant strains of the fungus. This highlights the critical need to investigate potential new antifungal medicines. It has been shown that alkaloids isolated from the leaves of Ruta graveolens L. are fungi toxic [145]. Flavonoids and quinoline alkaloids isolated from the roots of Waltheria indica L. showed that to have antifungal activity against Candida albicans [146]. Table 2 summarizes some selected medicinal plants that possess alkaloids with antimicrobial properties.

Plant and family	Common name	Part of plant	Extraction solvent	Method of detection	Bioactive compound	Ref.
Antibacterial
Alchornea laxiflora /Euphorbiaceae	Three-veined bead string, Lowveld bead string, Venda bead string,	Leaf	Methanol and distilled water	—	—	[147]
Amaryllis belladonna/Amaryllidaceae	Jersey lily	Bulb	Chloroform, Ethanol, and n-butanol	HPTLC	(-)-Amarbellisine, (-)-lycorine, (-)-pancracine, (+)-vittatine, (+)-11-hydroxyvittatine, and (+)-hippeastrine	[148]
Stephania glabra/Menispermaceae	Hairless tape vine	Tuber	Ethanol	—	gindarine, gindaricine, gindarinine, columbamine, jatrorrhizine and magnoflorine	[149]
Zanthoxylum spp./Rutaceae	Pricklyash	—	—	—	Quinoline, isoquinoline, indole, quinazoline, indolopyridoquinazoline	[143]
Eurycoma longifolia/Simaroubaceae	Tongkat Ali	Leaf	Acetone, methanol, and ethanol			[144]
Morus alba/Moraceae	Mulberry	Root	Water extract	NMR	piperidine	[150]
Glycyrrhiza glabra L./Fabaceae	Licorise	Aerial parts	Methanol	—	—	[151]
Ficus sycomorus/Moraceae	Mulberry Fig, Sycamore Fig	Leaf	Methanol	—	—	[152]
Telosma (Pergularia) pallida/Apocynaceae	Telosma vine	Air-dried roots	—	—	pergularinine and tylophorinidine	[153]
Lupinus angustifolius L./Fabaceae	Lupine	Aerial parts	Dichloromethane	GC-MS	13α-Hydroxylupanine (50.78%) and lupanine (23.55%)	[154]
Murraya koenigii (L) Spreng/Rutaceae	Curry tree	The stem barks	Petroleum ether	UV, IR, MS, and a series of 1D and 2D NMR	Benzoisofuranone and carbazole	[51]
Peganum harmala/Nitrariaceae	Wild rue, Syrian rue, esfand, espand, harmel	Root and seed	Methanolic extract	TLC	Pegamine, vasicine, harmine, harmane, harmaline, harmalol, and vasicinon	[155]
Phoenix dactylifera L./Arecaceae	Date palm	Leaf and pit	Methanol and acetone	—	—	[156]
Antifungal
Ruta graveolens L./Rutaceae	Rue, common rue, herb-of-grace	Leaf	Hexane	(1)H and (13)C NMR	1-methyl-2-[6'-(3″,4″-methylenedioxyphenyl)hexyl]-4-quinolone	[145]
Waltheria indica/Malvaceae	Sleepy morning	Aerial parts	Dichloromethane	COSY, HSQC, HMBC, NOESY NMR, UV, IR, and HRESIMS	Waltheriones and 5®-vanessine	[146]
Antiviral
Phellodendron amurense/Rutaceae	Amur cork tree	Bark	Aqueous and ethanol	—	Berberine	[157]
Moringa oleifera/Moringaceae	ben oil tree, drumstick tree, horseradish tree, and benzolive tree	Leaf	Water extract	LC-MS	Gentiatibetine	[158]
Nuphar lutea/Nymphaeaceae					thiobinupharidines and thiobinuphlutidines	[159]
Antiparasitic
Argemone Mexicana/Papaveraceae	Mexican poppy	Leaves and stems	Methanolic extract	Dragendorff’s reagent	Berberine	[160]
Spondias mombin/Anacardiaceae	Yellow mombin	Bark and leaves	Aqueous and ethanol	—	—	[161]

Table 2.

Selected medicinal plants possess antimicrobial activity based on their alkaloids as components.

In a study by Erdemoglu et al. [154], capillary GC-MS identified 15 alkaloids. 13α-hydroxylupanine (50.78%) and lupanine (23.55%) were assessed to be the significant alkaloids in the aerial parts of L. angustifolius. Ammodendrine, tetrahydrorhombifoline, isoangustifoline, α-isolupanine, 5,6-dehydrolupanine, 11,12-dehydrolupanine, 13α-tigloyloxylupanine, 13α-acetoxylupanine, angustifoline, 13α-isovaleroyloxylupanine, 13α-valeroyloxylupanine, 13α-cis-cinnamoyloxylupanine, and 13α-cis-cinnamoyloxy-17-oxolupanine were analyzed as the minor alkaloids of the substances in this plant. The alkaloid extract showed modest effectiveness against E. coli, while a strong point against B. subtilis, S. aureus, and P. aeruginosa. The extract was only moderately effective against Candida albicans and C. krusei [154]. Although native to the Middle East and Mediterranean regions, Peganum harmala has been introduced to Australia and the United States [155]. The alkaloids of P. harmala are concentrated in its roots and seeds. All 13 Gram-positive (S. pyogenes, S. epidermidis, S. aureus, L. monocytogenes B. pumilus, B. cereus, and B. anthracis) and Gram-negative (Brucella melitensis, P. aeruginosa, Salmonella typhi, Klebsiela pneumoniae, E. coli, and P. mirabilis) bacteria tested showed inhibition by methanol extract [155]. Papaver somniferum, belonging to the Papaveraceae botanical family, has been the subject of extensive research due to its benzylisoquinoline alkaloids (BIAs), which have been utilized for medicinal purposes since ancient times. It is notable for being the sole commercial source of morphine and codeine and is regarded as the model plant for BIA research. P. somniferum synthesizes vital alkaloids, such as sanguinarine, papaverine, and noscapine [162].

Native to Oman, Ficus sycomorus has had its leaf extracts investigated for their ability to eradicate Haemophilus influenzae, S. aureus, E. coli, and Proteus spp. [152]. Ficus sycomorus is abundant in flavonoids, alkaloids, tannins, and phenolic compounds. The leaves were subjected to methanol extraction, and subsequent extraction with various solvents. The disk diffusion technique results showed that at concentrations of 0.22–2.02 mg/mL, the crude leaf extracts showed antibacterial activity against E. coli, with inhibition diameters ranging from 0 to 9 mm [152].

The Apocynaceae plants, Catharanthus roseus, and Rauwolfia serpentina are known for their production of significant alkaloids, including serpentine, vinblastine, vincristine, ajmalicine, reserpine, and ajmaline. These plants are role models for understanding how monoterpene indole alkaloids (MIA) are synthesized. Considerable knowledge exists regarding the physiological and ecological factors producing MIA in C. roseus [37].

The date palm is widely distributed throughout the Arabian Peninsula and is recognized as a significant economic crop. Date palms possess various chemical compounds such as vitamins, flavonoids, steroids, alkaloids, tannins, and carbohydrates. Except for E. faecalis, both the methanol and acetone extracts showed potent antibacterial activity [156].

5. Alkaloids’ antibacterial mechanism of action

Alkaloids have been observed to affect various metabolic systems in animals, and their toxic mechanism of action can display considerable variability. Toxicity may present itself via enzymatic alterations that affect physiological functions, obstruction of DNA synthesis and repair mechanisms by intercalating with nucleic acids, or modulation of the nervous system. Various alkaloids can exert an influence on different physiological processes [37]. However, bactericidal drugs are those that, in the absence of confounding variables, result in a 99.9% reduction in bacterial viability at doses no higher than four times the MIC [96]. Most research shows that alkaloids are antibacterial, not bacteriostatic, though this might vary depending on the species of specific alkaloids (such as chelerythrine and prosopilosidine) [8, 15]. The MIC values of squalamine have been demonstrated to be bactericidal within 1–2 hours, killing 99.99% or more of gram-positive and gram-negative bacteria [8]. Their primary antibacterial methods involve blocking bacterial metabolism, altering membrane permeability, and blocking the creation of nucleic acids and proteins [17]. Techniques involving the controlled introduction of pathogens or herbivores, the physical or chemical stimulation of their presence, and the subsequent monitoring of gene expression, enzyme activity, and concentrations of precursors and the alkaloid itself have proven effective [37]. The distinct classes of alkaloids exhibit varying mechanisms of action as antibacterial agents [37]. The antibacterial properties of pergularinine and tylophorinidine, which belong to the indolizine class of alkaloids, are attributed to their ability to inhibit the dihydrofolate reductase enzyme, thereby impeding the synthesis of nucleic acids [153]. Agelasines alkaloids affect bacterial hemostasis by inhibiting the dioxygenase enzyme BCG 3185c, contributing to their antibacterial action. Agelasine D is an alkaloid with antimycobacterial activities, and its overexpression and binding affinity in studies led to the result mentioned above [163]. The respiratory inhibition effects of synthetic quinolone alkaloids, as well as the cell division inhibition effects of isoquinolines, including protoberberine, berberine, benzophenanthridine, and sanguinarine through perturbation of the Z-ring, have been documented. Additionally, the phenanthridine isoquinoline alkaloid ungeremine has been found to inhibit nucleic acid synthesis. In contrast, the indolizidine alkaloids pergularinine and tylophorinidine have been shown to suppress nucleic acid synthesis by inhibiting dihydrofolate reductase [37]. The mechanisms of action about antibacterial activity exhibit variation across distinct alkaloids. The following examples are being examined [16]:

1. Disruption of the bacterial membrane.

   Several alkaloids from herbal plants have been discovered to exhibit antimicrobial activity by disrupting the bacterial membrane. For example, herbal alkaloids like berberine and palmatine have been proven to cause bacterial cell death by rupturing their membrane [164, 165]. Additionally, squalamine is a polyamine alkaloid with a detergent-like mode of action, depolarizing Gram-positive bacteria membranes and disrupting Gram-negative bacteria’s outer membranes [16]. The cytoplasmic membrane is disturbed by phenanthroindolizidine alkaloids [166]. For instance, berberine attacked the mitochondrial membrane of fungi and resulted in cytoplasmic damage in Streptococcus agalactiae (CVCC 1886 strain, obtained from the Microbiological Lab of Sichuan Agricultural University, Ya'an, China), whereas liriodenine caused cytoplasmic changes and cell wall destruction in Paracoccidioides brasiliensis [9].

2. Interfering with cell division.

   Pergularinine and tylophorinidine, two phenanthroindolizidine plant alkaloids, can block the production of nucleic acids. Protein, RNA, and DNA synthesis rely on pyrimidine and purine precursors, produced by the crucial enzyme dihydrofolate reductase [16]. DNA-protein cross-linking and DNA cross-linking are two mechanisms through which certain alkaloids, such as aristolochic acids, can cause mutations [167]. Interaction with DNA is thought to be the primary mechanism by which quinoline alkaloids exert their antibacterial and antifungal effects [9]. Another example is berberine, which was effective against Actinobacillus pleuropneumoniae and Streptococcus agalactiae (CVCC 1886) by inhibiting DNA synthesis and preventing synthesis [168].

3. Bacterial enzyme and respiratory system inhibition:

   Alkaloids from herbal plants have been reported to inhibit bacterial enzymes and respiratory systems. For example, inhibiting the respiratory system of bacteria, including S. aureus, has been demonstrated for the alkaloid tetrandrine, which is present in several medicinal plants [15]. Additionally, berberine can inhibit bacterial enzymes like DNA gyrase leading to cell death [15]. Also, the alkyl methyl quinolone alkaloids exhibit potent and selective antibacterial properties against H. pylori using respiratory inhibition [169].

4. Modulating the expression of virulence genes.

   The regulatory protein ToxT has been identified in V. cholerae. It plays a crucial role in activating various virulence determinants, including the genes responsible for encoding virulence factors. Additionally, Yang et al. report that cholera toxin and ToxT co-regulated pilus [170]. The isoquinoline alkaloid known as virstatin has been found to effectively inhibit ToxT, which subsequently results in the inhibition of virulence factors. The research showed that it prevented V. cholerae from colonizing the intestines of newborn mice models [16].

   On the other hand, the majority of quinoline and indole-based antifungal and antibacterial alkaloids discovered in Asian angiosperms, respectively, target DNA, topoisomerases, and the cytoplasmic membrane as their primary sites of action [9].

6. Conclusions and future

Alkaloids comprise a vast and heterogeneous category of compounds that exhibit a broad-spectrum of biological functions that hold immense significance for plants, animals, and humans. These compounds possess remarkable pharmacological properties. The advent of antibiotic-resistant microorganisms has substantially compromised antibiotic effectiveness. To date, a new approach to tackling antibiotic resistance is urgently needed. In the coming years, bioactive compounds will likely be discovered using phytochemicals, which exhibit a variety of chemical structures and methods of action. Alkaloids exhibit varying primary functions across different plant species, and their metabolic profiles are often associated with distinct environmental factors and developmental cues, thereby providing evident adaptive advantages. Concerning potential toxicity to other organisms or the production of bioactive metabolites for therapeutic applications, the variation in plant alkaloid metabolism and accumulation is crucial. Alkaloids are effective in this review report as an alternate therapy for combating the emergence and spread of multidrug-resistant infections and the harmful effects of some antibiotics. The following compounds have been identified as primary candidates due to their MIC of less than 1 μg/mL: 8-Acetylnorchelerythrine, cryptolepine, sampangine, 8-hydroxydihydrochelerythrine, 6-methoxydihydrosanguinarine, 2′-nortiliacorinine, tiliacorine, rhetsisine, pendulamine A and B, tylophorinine, tryptanthrin, viroallosecurinine, and vallesamine.