Antibacterial and Antifungal Alkaloids from Asian Angiosperms: Distribution, Mechanisms of Action, Structure-Activity, and Clinical Potentials

Abstract

The emergence of multidrug-resistant bacteria and fungi requires the development of antibiotics and antifungal agents. This review identified natural products isolated from Asian angiosperms with antibacterial and/or antifungal activities and analyzed their distribution, molecular weights, solubility, and modes of action. All data in this review were compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem, and a library search from 1979 to 2022. One hundred and forty-one antibacterial and/or antifungal alkaloids were identified during this period, mainly from basal angiosperms. The most active alkaloids are mainly planar, amphiphilic, with a molecular mass between 200 and 400 g/mol, and a polar surface area of about 50 Ų, and target DNA and/or topoisomerase as well as the cytoplasmic membrane. 8-Acetylnorchelerythrine, cryptolepine, 8-hydroxydihydrochelerythrine, 6-methoxydihydrosanguinarine, 2′-nortiliacorinine, pendulamine A and B, rhetsisine, sampangine, tiliacorine, tryptanthrin, tylophorinine, vallesamine, and viroallosecurinine yielded MIC ≤ 1 µg/mL and are candidates for the development of lead molecules.

1. Introduction

The resistance of bacteria and fungi to antimicrobial agents necessitates the continuous development of antibiotics and antifungal agents with original chemical frameworks that may come from flowering plants. The flowering plants also termed angiosperms comprise 11 major taxa or clades grouped into three groups: (i) basal angiosperms including Protomagnoliids, Magnoliids, Monocots, Eudicots; (ii) core angiosperms including Core Eudicots, Rosids, Fabids, Malvids; and (iii) upper angiosperms including Asterids, Lamiids, and Campanulids [1]. Within each clade, plants yield both non-specific and specific secondary metabolites such as alkaloids to control the growth of phytopathogenic bacteria and fungi. These antimicrobial principles fall into two main groups: phytoanticipins and phytoalexin. Phytoanticipins are antimicrobial compounds in plants that are present before phytopathogenic microorganism challenge or inactive immediate precursors stored in healthy tissues that are converted into antimicrobial metabolites known as phytoalexins [2]. Phytoanticipins and phytoalexins containing primary, secondary, tertiary, or quaternary amines are called alkaloids, which belong to various chemical classes, principally amides, indoles, piperidines, quinolines, isoquinolines, pyrrolidines, imidazoles, diterpenes, sesquiterpeness, and steroidal alkaloids [3].

Phytopathogenic Gram-negative bacteria are more resistant to alkaloids than Gram-positive bacteria due, at least in part, to an outer hydrophilic and negatively charged layer of lipopolysaccharides [4]. In Gram-negative bacteria, porins allow for the entry of water and nutrients through the outer layer and hydrophilic and amphiphilic xenobiotics with a molecular mass below 600 g/mol xenobiotics without nutritional or physiological benefit or toxins are actively cleared from the cytoplasm by efflux pumps [5]. The assessment of the antibacterial and antifungal strength of isolated secondary metabolites in vitro is qualitatively appreciated by the measurement of the diameter of an inhibition zone and quantitively based on the minimum inhibiting concentration (MIC), and several thresholds of activity have been proposed [6,7,8,9]. Angiosperms produce alkaloids that inhibit the growth of both Gram-positive, Gram-negative bacteria, yeasts, and filamentous fungi and these principles are of potential therapeutic value. Among the factors that influence the antibacterial or antibacterial strength, and the targets of alkaloids are the molecular mass and water solubility [10].

Over the last 80 years, enormous research efforts have been devoted to the aim of identifying antibiotic or antifungal lead molecules in flowering plants globally, but to date, none of these have been developed as drugs. The present work attempts to provide a comprehensive review of the main findings regarding the antibacterial and antifungal alkaloids from Asian angiosperms. All data in this review were compiled from Google Scholar, PubMed, Science Direct, Web of Science, ChemSpider, PubChem, and a library search from 1979 to 2022 and were analyzed to address the following points: (i) distribution; (ii) strongest principles identified; (iii) spectrum of activity; (iv) influence of molecular mass, water solubility, and polar surface; (v) the mode of action; (vi) structure–activity; and (vii) efflux pump inhibition.

2. Distribution

Regarding the distribution of antibacterial and antifungal alkaloids from Asian angiosperms (Figure 1), the following could be observed:

• All clades yielded antibacterial and/or antifungal alkaloids, except for the Rosids.

• Most antibacterial and/or antifungal alkaloids can be found in basal angiosperms, which are isoquinolines.

• Some clades yielded a specific class of antibacterial and/or antifungal alkaloids such as the Amaryllidaceae alkaloids in the Monocots, phenanthrene alkaloid in the Magnoliids, Securinega alkaloids in Fabids, carbazoles in the Malvids, and monoterpene indole alkaloids in the Lamiids.

• Core angiosperms and upper angiosperms use various classes of alkaloids and phytoalexins.

• Most antibacterial and/or antifungal alkaloids have been isolated from medicinal plants (Table 1, Table S1).

• Tripathi et al. (1994) observed changes in the antibacterial alkaloid concentrations in plants over time [11].

Figure 1.

The phylogenetic distribution of antibacterial and/or antifungal alkaloids in angiosperms.

Table 1.

The chemical structures of antibacterial and/or antifungal alkaloids and their botanical origin.

CLASS Compound	Chemical Structure	Genus, Species	Family
ACRIDANONES
1-Hydroxy-3,4-dimethoxy-10-methylacridan-9-one		Limonia acidissima L.	Rutaceae
1-Hydroxy-3-methoxy-10-methylacridan-9-one		Limonia acidissima L.	Rutaceae
AMARYLLIDACEAE ALKALOIDS
Crinamine		Crinum asiaticum L.	Amaryllidaceae
Lycoricidine		Lycoris radiata (L’Hér.) Herb.	Amaryllidaceae
Lycorine		Lycoris radiata (L’Hér.) Herb.	Amaryllidaceae
Narciclasine		Lycoris radiata (L’Hér.) Herb.	Amaryllidaceae
Tazettine		Narcissus tazetta L.	Amaryllidaceae
APORPHINES
Anonaine		Michelia alba DC.	Magnolicaceae
Artabotrine		Artabotrys suaveolens (Bl.) Bl.	Annonaceae
Bulbocapnine		Corydalis bulbosa DC.	Fumariaceae
Dicentrinone		Phoebe lanceolata (Nees) Nees	Lauraceae
Isoboldine		Corydalis bulbosa DC.	Fumariaceae
Lanuginosine		Eupomatia laurina R. Br.	Eupomatiaceae
Liriodenine		Cananga odorata Hook. F. & Thomson	Annonaceae
Lysicamine		Phoebe grandis (Nees) Merr.	Lauraceae
Magnoflorine		Mahonia bealei (Fortune) Carrière	Papaveraceae
Nordicentrine		Phoebe lanceolata (Nees) Nees	Lauraceae
O-Methylmoschatoline		Cananga odorata (Lam.) Hook. F. & Thomson	Annonaceae
Roemerine		Papaver rhoeas L.	Papaveraceae
Sampangine		Eupomatia laurina R. Br.	Eupomatiaceae
Thailandine		Stephania venosa (Bl.) Spreng	Menispermaceae
Xylopine		Artabotrys suaveolens (Bl.) Bl.	Annonaceae
BENZOPHENANTHRIDINES
8-Acetylnorchelerythrine		Toddalia asiatica (L.) Lam.	Rutaceae
Avicine		Toddalia asiatica (L.) Lam.	Rutaceae
Chelerythrine		Macleaya cordata (Willd.) R. Br.	Papaveraceae
Corynoline		Corydalis incisa (Thunb.) Pers.	Fumariaceae
Dihydrochelerythrine		Macleaya cordata (Willd.) R. Br.	Papaveraceae
Dihydrosanguinarine		Macleaya cordata (Willd.) R. Br	Papaveraceae
8-Hydroxydihydrochelerythrine		Chelidonium majus L.	Fumariaceae
8-Hydroxydihydrosanguinarine		Chelidonium majus L.	Fumariaceae
6-Methoxydihydrosanguinarine		Chelidonium japonicum Thunb	Fumariaceae
Nitidine		Zanthoxylum L.	Rutaceae
Norchelerythrine		Toddalia asiatica (L.) Lam.	Rutaceae
Norsanguinarine		Fumaria indica Pugsley	Fumariaceae
Rhoifoline B		Toddalia asiatica (L.) Lam.	Rutaceae
Sanguinarine		Fumaria officinalis L.	Fumariaceae
Stylopine		Fumaria officinalis L.	Fumariaceae
CARBAZOLES
3,3′-[Oxybis(methylene)]bis(9-methoxy-9H-carbazole)		Murraya koenigii (L.) Spreng.	Rutaceae
Clausamine A		Clausena harmandiana (Pierre) Guillaumin	Rutaceae
Clausamine B		Clausena harmandiana (Pierre) Guillaumin	Rutaceae
Clausine F		Clausena harmandiana (Pierre) Guillaumin	Rutaceae
Clauszoline N		Clausena harmandiana (Pierre) Guillaumin	Rutaceae
3-Formylcarbazole		Clausena mexicana Burm.f.	Rutaceae
3-Formyl-1-methoxycarbazole		Murraya koenigii (L.) Spreng.	Rutaceae
Girinimbine		Murraya koenigii (L.) Spreng.	Rutaceae
Glycozolidol		Glycosmis pentaphylla (Retz.) DC.	Rutaceae
Harmane		Murraya mexicana (L.) Jack	Rutaceae
Koenimbine		Murraya koenigii (L.) Spreng.	Rutaceae
Koenigine		Murraya koenigii (L.) Spreng.	Rutaceae
Lansine		Micromelum pubescens Bl.	Rutaceae
Murrayamine J		Murraya mexicana (L.) Jack	Rutaceae
BENZYLISOQUINOLINES
Reticuline		Annona squamosa L.	Annonaceae
Fuyuziphine		Fumaria indica Pugsley	Fumariaceae
BISBENZYLISOQUINOLINES
2′-Nortiliacorinine		Tiliacora triandra Diels	Menispermaceae
Tetrandrine		Cyclea barbata Miers	Menispermaceae
Tiliacorine		Tiliacora triandra Diels	Menispermaceae
Tiliacorinine		Tiliacora triandra Diels	Menispermaceae
DITERPENE ALKALOIDS
8-Acetylheterophyllisine		Delphinium denudatum Wall. Ex Hook. F. & Thomson yields	Ranunculaceae
Panicutine		Delphinium denudatum Wall. Ex Hook. F. & Thomson yields	Ranunculaceae
Vilmorrianone		Delphinium denudatum Wall. Ex Hook. F. & Thomson yields	Ranunculaceae
HASUBANANS
Glabradine		Stephania glabra (Roxb.) Miers	Menispermaceae
IMIDAZOLES
Allantoin		Tournefortia sarmentosa Lam	Borraginaceae
INDOLOQUINAZOLINES
Dehydroevodiamine		Euodia rutaecarpa Benth	Rutaceae
Evodiamine		Euodia rutaecarpa Benth	Rutaceae
Tryptanthrin		Indigofera tinctoria L.	Fabaceae
INDOLOQUINOLINES
Cryptolepine		Cryptolepis sanguinolenta (Lindl.) Schltr.	Apocynaceae
MONOTERPENE INDOLE ALKALOIDS
Alstoniascholarine A		Alstonia scholaris (L.) R.Br.	Apocynaceae
Alstoniascholarine E		Alstonia scholaris (L.) R.Br.	Apocynaceae
Alstoniascholarine J		Alstonia scholaris (L.) R.Br.	Apocynaceae
Cadambine		Neolamarckia cadamba (Roxb.) Bosser	Rubiaceae
Ibogaine		Ervatamia mexicana (L.) Burkill	Apocynaceae
3-Oxocoronaridine		Ervatamia mexicana (L.) Burkill	Apocynaceae
5-Oxocoronaridine		Ervatamia mexicana (L.) Burkill	Apocynaceae
Strictosidine		Guettarda speciosa L.	Rubiaceae
Vallesamine		Ervatamia mexicana (L.) Burkill	Apocynaceae
Voacamine		Ervatamia mexicana (L.) Burkill	Apocynaceae
Voacangine		Ervatamia exicana (L.) Burkill	Apocynaceae
Vobasine		Ervatamia mexicana (L.) Burkill	Apocynaceae
Tubotaiwine		Alstonia scholaris (L.) R.Br.	Apocynaceae
PHENANTHRENE ALKALOIDS
Aristolochic acid		Aristolochia L.	Aristolochiaceae
Aristolactam N-(6′-trans-p-coumaroyl)-β-d-glucopyranoside		Aristolochia L.	Aristolochiaceae
1-N-monomethylcarbamate-argentinine-3-O-β-d-glucoside		Stephania succifera H.S. Lo & Y. Tsoong	Meninspermaceae
PHENANTHROINDOLIZIDINE ALKALOIDS
7-Demethoxytylophorine		Cynanchum atratum Bunge	Asclepiadaceae
Tylophorinine		Tylophora indica (Burm.f.) Merr.	Asclepiadaceae
Tylophorinidine		Tylophora indica (Burm.f.) Merr	Asclepiadaceae
PIPERINE ALKALOIDS
Piperine		Piper nigrum L.	Piperaceae
Piperlongumine		Piper longum L.	Piperaceae
PHTHALIDES
Adlumidine		Fumaria officinalis L. t	Fumariaceae
Bicuculline		Corydalis bulbosa DC.	Fumariaceae
PROTOBERBERINES
Berberine		Coptis chinensis Franch.	Ranunculaceae
Jatrorrhizine		Coptis chinensis Franch.
Palmatine		Corydalis exicana (Thunb.) Pers.	Fumariaceae
Sinactine		Fumaria officinalis L.	Fumariaceae
PYRROLIDINES
Brachyamide B		Piper nigrum L.	Piperaceae
Isopiperolein B		Piper nigrum L.	Piperaceae
N-[9-(3,4-Methylenedioxyphenyl)-2E,4E,8E-nonatrienoyl]pyrrolidine		Piper nigrum L.	Piperaceae
Pandamarilactonine A		Pandanus odorus Ridl.	Pandanaceae
Trachyone		Piper nigrum L.	Piperaceae
QUINOLINONES
Antidesmone		Waltheria indica L.	Malvaceae
Evocarpine		Euodia rutaecarpa Benth	Rutaceae
1-Methyl-2-nonyl-4(1H)-quinolone		Euodia rutaecarpa Benth	Rutaceae
1-Methyl-2-[(Z)-5′-pentadecenyl]-4(1H)-quinolone		Euodia rutaecarpa Benth	Rutaceae
Waltherione C		Waltheria indica L.	Malvaceae
QUINOLIZIDINE ALKALOIDS
6,6′-Dihydroxythiobinupharidine		Nuphar japonica DC.	Nymphaeaceae
7-Hydroxylupanine		Sophora flavescens Aiton	Fabaceae
N-Butylcytisine		Sophora flavescens Aiton	Fabaceae
SECURINEGA ALKALOIDS
Securinine		Flueggea virosa (Roxb. Ex Willd.) Royle	Phyllanthaceae
Viroallosecurinine		Flueggea virosa (Roxb. Ex Willd.) Royle	Phyllanthaceae
MISCELLANEOUS PIPERINE ALKALOIDS
Dihydrodioscorine		Dioscorea bulbifera L.	Dioscoreaceae
Haloxyline B		Haloxylon salicornicum (Moq.) Bunge ex Boiss.	Chenopodiaceae
Pandamarilactone-1		Pandanus odorus Ridl.	Pandanaceae
SIMPLE QUINOLINE ALKALOIDS
Camptothecin		Gomphandra Wall. Ex Lindl.	Icacinaceae
Dictamine		Dictamnus albus L.	Rutaceae
γ-Fagarine		Dictamnus albus L.	Rutaceae
4-Methoxy-2-phenylquinoline		Lunasia amara Blanco	Rutaceae
4-Methylquinoline		Citrullus colocynthis (L.) Schrad.	Cucurbitaceae
Robustine		Dictamnus albus L.	Rutaceae
PROTOBERBERINES
Pendulamine A		Polyalthia longifolia (Sonn.)	Annonaceae
Pendulamine B		Polyalthia longifolia (Sonn.)	Annonaceae
PROTOPINES
Allocryptopine		Macleaya cordata (Willd.) R. Br	Papaveraceae
Protopine		Argemone mexicana L.
SPIROBENZYLISOQUINOLINES
(+)-Fumariline		Fumaria officinalis L.	Fumariaceae
Fumarophycine		Fumaria officinalis L. yields	Fumariaceae
(+)-Parfumine		Fumaria indica Pugsley	Fumariaceae
STEROIDAL ALKALOIDS
Conimine		Holarrhena pubescens Wall. Ex G. Don	Apocynaceae
N-Formylconessimine		Holarrhena pubescens Wall. Ex G. Don	Apocynaceae

3. The Strongest Antibacterial and/or Antifungal Alkaloids Identified and Spectrum of Activity

Rios and Recio defined a crude extract with MIC greater than 1000 µg/mL as inactive and suggested interesting antibacterial activity for MICs of 100 µg/mL or lower [6]. Previously, Fabry et al. (1998) defined crude active extracts as having MIC values below 8000 µg/mL [7], while more recently, Kuete (2010) defined crude extracts with MIC values less than 100 µg/mL as active and MICs above 625 µg/mL as weakly active [9]. Here, a compound was very strongly antibacterial or antifungal for a MIC value below or equal to 1 µg/mL; strongly antibacterial (or antifungal for a MIC value above 1 and below or equal to 50 µg/mL; moderately antibacterial or antifungal for a MIC from 50 and below 100 µg/mL; weakly antibacterial (or antifungal) for a MIC from 100 and below 500 µg/mL; very weakly antibacterial or antifungal for a MIC ranging from 500 to below 2500 µg/mL; and inactive for a MIC value above 2500 µg/mL. Following this classification, 8-acetylnorchelerythrine, cryptolepine, 8-hydroxydihydrochelerythrine, 6-methoxydihydrosanguinarine, 2′-nortiliacorinine, pendulamine A and B, rhetsisine, sampangine, tiliacorine, tryptanthrin, tylophorinine, vallesamine, and viroallosecurinine showed very strong activities (Table S2).

Looking at the spectrum of activity, most alkaloids showed activity against Gram-positive bacteria, followed by Gram-negative bacteria, yeasts, filamentous fungi, and mycobacteria (Table S2).

4. Influence of Molecular Mass

The molecular mass of natural products dictates their ability to fit in the catalytic pockets of enzymes and to cross biological membranes. Here, low molecular mass molecules were defined with a molecular mass below 200 g/mol; medium molecular mass molecules were defined with a molecular mass from 200 to 400 g/mol; and high molecular mass molecules were defined for a molecular mass above 400 g/mol. Following this classification, we noted that principles with very strong activity against bacteria and fungi had a molecular mass mainly from 200 to 400 g/mol whereas very strong repressors of mycobacteria mainly had a mass above 400 g/mol (Table S2).

5. Influence of Solubility and Polar Surface

Because solubility is a fundamental criterion in which to consider the efficacy of alkaloids, there is need to use mathematical values. Log P is equal to the ratio of concentrations of a compound between octanol and water. Hydrophilic compounds (hydrophilic) have low or negative values (about −3) (compounds are mainly found in the water phase). Mid-hydrophilic compounds have a Log P close to 0 (the compound is equally partitioned between the octanol and water layers). Non-hydrophilic (hydrophobic, liposoluble) compounds have a high Log P (up to about 7) (note that lipophilic alkaloids tend to remain in and destabilize the cytoplasmic membrane of bacteria and fungi). However, Log P is only relevant for non-ionizable principles and for an ionized substance, a Log D is preferable (in terms of ADME), but the pH must be fixed. In some databases, one can find a Log P of 3 for the ionic alkaloid berberine, suggesting a lipophilic substance, which is not sensible. Since compounds destined for pharmaceutical development will mainly be exposed to physiological pH and often a weak base or a weak acid, we defined, at pH 7.4, lipophilic compounds for a negative Log D value of 4, amphiphilic (mid-polar) compounds for a Log D up to about 4.5, and lipophilic for a Log D above 4.5. Note that the Log D values given here are predicted values. Following this classification, we noted that principles with very strong activity against bacteria and fungi were mainly amphiphilic, whereas very strong antimycobacterial agents were mainly lipophilic (Table S2). Most antibiotics with very strong antibacterial and/or antifungal effects have a polar surface area around 50 Å (Table S2).

6. Mechanisms of Action and Structure-Activity Relationships

Most antibacterial and/or antifungal alkaloids from Asian angiosperms either bear a quinoline or an indole framework and the main mechanisms of action involve the targeting of the DNA, topoisomerases, and cytoplasmic membrane.

6.1. Alkaloids Targeting DNA and/or Topoisomerase

Some alkaloids including aristolochic acids bind to DNA or pyrrolizidine alkaloids, which form DNA cross-linking and DNA-protein cross-linking, leading to mutations [12,13]. Planar alkaloids tend to intercalate with bacterial DNA such as sanguinarine DNA [14], canthin-6-one [15], carbazoles [16], and tryptanthrin [17]. Cryptolepine intercalates into DNA and stimulates DNA cleavage by II [18] and was bacteriolytic for Staphylococcus aureus (NCTC 10788) [19]. Evodiamine inhibits topoisomerase I by stabilizing the enzyme-DNA covalent complex [20].

The mode of antibacterial and antifungal action of quinoline alkaloids mainly evokes interaction with DNA. Dictamnine binds to DNA under UV light [21]. Camptothecin stabilizes the topoisomerase I–DNA complex [22]. Liriodenine blocks topoisomerase II [23]. Berberine was active against Actinobacillus pleuropneumoniae and Streptococcus agalactiae (CVCC 1886) via DNA synthesis inhibition and the blockage of synthesis [24,25]. Anonaine induces DNA damage [26] as well as magnoflorine [27]. Aporphine alkaloids are planar and intercalate DNA and inhibit topoisomerase [28] as well as Amaryllidaceae alkaloids [29]. The quaternary ammonium ion of protoberberine alkaloids and their heterocyclic planar framework account for topoisomerase I inhibition [30].

During bacterial division, topoisomerase IV catalyzes the relaxation of the DNA chain and 6,6′-dihydroxythiobinupharidine blocks this enzyme in S. aureus [31]. Phenanthroindolizidine alkaloids interact with DNA [32]. In Gram-positive bacteria, topoisomerase IV is a target for bactericidal quinolone antibiotics [33]. Asian angiosperms produce a vast array of quinoline, isoquinoline, piperidine, and quinolizidine alkaloids, representing a fascinating reservoir of topoisomerase IV inhibitors.

In summary, heterocyclic alkaloids with low to medium molecular mass, close to planar or planar, with the presence of a few hydroxy or ketone groups, almost always target DNA and/or RNA in bacteria and fungi. From this perspective, quinazolone alkaloids in the family Hydrangeaceae (order Saxifragales; clade Core Eudicots) could be examined for their antibacterial and or antifungal properties.

6.2. Alkaloids Targeting the Cytoplasmic Membrane

Phenanthroindolizidine alkaloids disturb the cytoplasmic membrane integrity [34]. The long alkyl chain of piperine and piperlongumine could penetrate the membrane of bacteria and fungi. In Candida albicans, piperine affects the membrane integrity, leading to oxidative stress followed by cell cycle arrest and apoptosis [35]. Marques et al. (2010) presented evidence that amides were more active against Cladosporium cladosporoides when the non-substituted aromatic ring, single double bonds, and substitution of nitrogen with alkyl groups were present [36]. In fungi, berberine targets the mitochondrial membrane [24]. Liriodenine in Paracoccidioides brasiliensis evoked cytoplasmic alterations and damage to the cell wall [37] while berberine evoked cytoplasmic insults in Streptococcus agalactiae (CVCC 1886) [34] and targeted the mitochondrial membrane of fungi [25].

6.3. Miscellaneous Targets

Aristolochic acids inhibited the H⁺-ATPase-mediated proton pump in E. coli [12]. Securinine induces mitotic block in cancer cells by binding to tubulin and inhibits microtubule assembly [38], therefore, microtubules could be involved in the antibacterial and/or antifungal properties of cytotoxic monoterpenoid indole alkaloids.

7. Efflux Pumps Inhibitors

P. aeruginosa and Gram-negative bacteria can resist a broad spectrum of natural products because they have extra classes of efflux pumps such as ABC (ATP binding cassette), RND (resistance nodulation cell-division), MF (major facilitator), SMR (small multidrug resistance) and MATE (multidrug and toxic compound extrusion) pumps [39]. ABC efflux pumps located in the cytoplasmic membrane of both Gram-positive and Gram-negative bacteria that use the energy derived from ATP hydrolysis to expel xenobiotics. RND efflux pumps located in the cytoplasmic and outer membrane of the Gram-negative bacteria (specific to Gram-negative bacteria) that expel xenobiotics using the H⁺ gradient (antiporters). MF efflux pumps located in the cytoplasmic membrane of both Gram-positive and Gram-negative bacteria that expel xenobiotics using the H⁺ gradient (antiporters). SMR efflux pumps located in the cytoplasmic membrane of both Gram-positive and Gram-negative bacteria that expel xenobiotics using the H⁺ gradient (antiporters). MATE efflux pumps located in the cytoplasmic membrane and are antiporters (the exit of the xenobiotic coincides with the entry of a Na⁺).

Tryptanthrin inhibits efflux P-glycoprotein in Caco-2 cells [16] and as such may inhibit bacteria and or fungal efflux pumps. Apocynaceous monoterpene indole alkaloids are often vasorelaxant [40], and therefore, with some inhibition levels of bacterial and or fungal efflux-pumps. For instance, the reserpine from Rauvolfia serpentina (L.) Benth. ex Kurz decreased the resistance of S. aureus (1199B, NorA hyperproducer) to ciprofloxacin and norfloxacin [10]. Reserpine is a calcium channel antagonist and an inhibitor of efflux pumps in Gram-negative bacteria and mycobateria [41]. From Rauvolfia serpentina (L.) Benth. ex Kurz, ajmaline and yohimbine are neuroactive and efflux pump inhibitors in Gram-negative bacteria [42]. Verapamil is another example of a calcium channel antagonist that inhibits the efflux pump in bacteria [42]. The reason why calcium channel antagonists have the tendency to inhibit the bacterial efflux pump could be because of the correlations between the bacterial efflux pumps and bacterial calcium transport [43]. Tetrandrine, which is a calcium channel antagonist in mammalian cells, inhibited the efflux pumps in S. aureus Rv2459 (jefA), Rv3728, and Rv3065 (mmr) efflux pumps in Mycobacterium species [44]. Therefore, natural products known for being calcium channel inhibitors should be screened as antibiotic potentiators. 4′-O-Methyldopamine inhibits NorA [45], showing that N-caffeoylphenalkylamide with the strongest efflux pump inhibitor activities presented hydroxyl substitution on the aromatic rings of the caffeic acid part and methoxy substitution on the aromatic ring of the dopamine moiety, which led to an increase in activity. Dopamine is a neurotransmitter, and it could be argued that neuroactive principles are a first line candidate for the development of efflux pump inhibitors. L-dopa increased the resistance of C. neoformans toward amphotericin B [46]. In line, erythrinan-type alkaloids and amide alkaloids in the family Piperaceae interact with GABAergic receptors and as such may be able to inhibit bacterial efflux pumps as in pellitorine, which at 16 µg/mL increased the sensitivity of S. aureus (RN4220) to erythromycin at 16 µg/mL via inhibition of the efflux pumps [5]. Canthin-6-one has a chemical structure with some similarity with serotonin and thus might be able to inhibit bacteria and/or fungal efflux pumps. In mammalian cells, tryptanthrin inhibits the expression of P-glycoprotein efflux pumps [46] and one could investigate its effect on the expression of efflux pumps in bacteria and fungi.

8. Amide Alkaloids

8.1. Simple Amide Alkaloids

Plants in the order Piperales (clade Magnoliids) yield antibacterial amide alkaloids with strong activity against Gram-positive bacteria (Figure 1). Pellitorine inhibited the growth of Bacillus sphaericus (ATCC 14577), Bacillus subtilis (ATCC 6051), Staphylococcus aureus (ATCC 9144), Escherichia coli (ATCC 25922), Pseudomonas syringae (ATCC 13457), and S. typhimurium (ATCC 23564) with the MIC values of 25, 12.5, 20, 150, 75, and 200 µg/mL, respectively [47]. Pellitorine (50 µg/disk) inhibited the growth of Listeria monocytogenes with an inhibition zone diameter of 9 mm and the MIC value of 500 µg/mL [48]. Pellitorine (20 µL of a 2 µg/mL solution/6 mm well) inhibited the growth of Aspergillus flavus, Aspergillus fumigatus, Coniophora puteana, Fibrophoria vaillentii, Fusarium proliferatum, and Rhisopus sp. with the inhibition zone diameters of 27, 29, 26, 28, 29, and 27 mm, respectively [49]. Piperlonguminine suppressed B. sphaericus (ATCC 14577), B. subtilis (ATCC 6051), S. aureus (ATCC 9144), E. coli (ATCC 25922), P. syringae (ATCC 13457), and S. typhimurium (ATCC 23564) with the MIC values of 20, 9, 12.5, 150, 75, and 175 µg/mL, respectively [47]. Piperlonguminine inhibited Mycobacterium tuberculosis with a MIC value of 50 µg/mL [50]. 8Z-N-isobutyleicosatrienamide and pellitorine had moderate potencies with S. aureus (MIC: 34 µM) [51]. Pellitorine restrained M. tuberculosis (H₃₇Ra) with the MIC value of 25 µg/mL [52]. di-p-Coumaroyl-caffeoylspermidine weakly inhibited the mycelial growth of Pyrenophora avenae and Blumeria graminis [53]. In the clade Clampanulids, Spilanthes paniculata Wall. ex DC yielded N-Isobutyl-2 (E), 6 (Z), 8 (E)-decatrienamide (also known as spilanthol), which was bactericidal for Streptococcus mutans with MIC/MBC values of 125/125 µg/mL and weakly repressed C. albicans (ATCC 10231) [44]. The condensation of ferulic acid and dopamine yielded N-trans-feruloyl-4-methyldopamine 200 µg/disk that developed halos with a broad-spectrum of bacteria [54] and increased the susceptibility of multidrug-resistant S. aureus (overexpressing the multidrug efflux transporter NorA) to norfloxacin at 100 μg/mL [44].

8.2. Cyclopeptides

Plants in the Fabids and Malvids produce broad-spectrum antibacterial cyclic peptides such as frangulanine, which inhibited the growth of S. aureus, B. subtilis, E. faecium, E. coli, E. cloacae, S. typhimurium, and P. aeruginosa with the MIC values of 50, 50, 25, 6.2, 50, 50, 0.7, and 25 µg/mL, respectively [55]. Frangulanine inhibited the growth of C. albicans and Saccharomyces cerevisae with the minimum amounts of 25 and 50 µM, respectively [56]. Nummularine H isolated from the roots of Ziziphus mauritiana Lam. (family Celastraceae; order Celastrales; clade Fabids) inhibited the growth of M. tuberculosis (H₃₇Ra) with the MIC of 4.5 μM [57].

9. Indole Alkaloids

9.1. Simple Indoles

9.1.1. Brassicaceous Indoles

Plants in the family Brassicaceae yield antifungal sulfurated indole alkaloids such as caulilexin A from Brassica oleracea L. and at the concentration of 5 × 10⁻⁴ M, inhibited the growth of Leptosphaeria maculans, Sclerotinia sclerotiorum, and Rhizoctonia solani by 55, 100, and 100%, respectively [58]. The thiazoyl-substituted indole camalexin was active against Alternaria brassicae (MIC: 80 µg/mL) [59].

9.1.2. β-Carbolines

The condensation of tryptophan and oxaloacetaldehyde yields strong broad-spectrum antibacterial and antimycobacterial β-carboline alkaloids in the clades Malvids and Lamiids. Canthin-6-one restrained the growth of S. aureus (1199B), S. aureus (XU212), and S. aureus (ENRSA-15) with the MIC values of 8, 8, and 32 µg/mL, respectively [60] as well as Mycobacterium fortuitum (ATCC 6841), Mycobacterium smegmatis (ATCC 14468), M. smegmatis (mc²22700), Mycobacterium phlei (ATCC 111758), and Mycobacterium abcessus (ATCC 19977) with the MIC values of 16, 8, 8, 8, and 16 µg/mL, respectively [60]. Rhetsinine very strongly suppressed Xanthomonas oryxae pv oryzae, Xanthomonas oryxae pv oryzicola with the EC₅₀ values of 1 and 4.5 µg/mL, respectively [61]. The condensation of 2 β-carboline yielded borrerine yields in Borreria verticillata (L.) G. Mey. (clade Lamiids), which at the concentration of 50 µg/mL inhibited the growth of S. aureus and at 6 µg/mL restrained Vibrio cholerae [62].

9.1.3. Carbazoles

The condensation of anthranilic acid and malonyl-CoA yields quinolinones that after prenylation and cyclization yield carbazole alkaloid phytoalexins in the family Nitrariaceae and Rutaceae in the order Sapindales (clade Malvids) (Figure 1). One such carbazole is glycozolidol (also known as 6-hydroxy-2-methoxy-3-methylcarbazole; 200 µg/mL/well), which restrained S. aureus, Bacillus firmis, S. lutea, Agrobacterium tumefaciens, and Proteus vulgaris [63]. 3-Formylcarbazole moderately inhibited the growth of Mycobacterium sp. [64]. Clausamine A (Log D = 3.9 at pH 7.4; molecular mass = 293.3 g/mol) inhibited the growth of MRSA (SK1), S. aureus (TISTR 1466), E. coli (TISTR 780), and S. typhimurium (TISTR 292) with the MIC values of 8, 32, 128, and 128 µg/mL, respectively [65]. Clausamine B very strongly inhibited the growth of MRSA (SK1) (MIC: 0.2 µg/mL) [65]. Clauszoline N inhibited the growth of MRSA (SK1), E. coli (TISTR 780), and S. typhimurium (TISTR 292) with the MIC values of 16, 64, and 128 µg/mL, respectively [65]. The prenylated carbazole clausine F very strongly inhibited MRSA (SK1) and S. aureus (TISTR 1466) with the MIC values of 4 µg/mL, respectively, and was moderately active for E. coli (TISTR 780) and S. typhimurium (TISTR 292) [65]. In the Rutaceae, lansine yielded a MIC of 14.3 µg/mL against M. tuberculosis (H37Rv) [66]. Murrayamine J restrained S. aureus (ATCC 29213), Bacillus cereus (IIIM 25) with the IC₅₀ values of 11.7 and 23.2 µM [67]. The prenylated carbazole girinimbine was active against B. cereus (IIIM 25) with the IC₅₀ value of 3.4 µM as well as S. aureus and Aspergillus niger with the MIC values of 3.1 and µg/mL, respectively [68]. Koenimbine repressed S. aureus (ATCC 29213) and B. cereus (IIIM 25) with IC₅₀ values of 17 and 22.5 µM [67] and koenigine was active against a variety of Candida sp. (MIC₉₀: 12.5–100 μg/mL) [68]. 3-Formyl-1-1methoxycarbazole moderately repressed S. aureus, B. subtilis, E. coli, P. vulgaris, A. niger, and C. [68]. 3,3′-[Oxybis(methylene)]bis(9-methoxy-9H-carbazole) inhibited the growth of Proteus vulgaris and C. albicans with the MIC values of 6.2 and 25 µg/mL, respectively [69].In the Nitrariaceae, harmane is very strongly active against Vibrio anguillarum (MIC: 3.1 µg/mL), [70]. In a subsequent study, harman weakly inhibited the growth of A. niger, C. albicans (Neenah, 2010), Cryptococcus gattii, and Cryptococcus neoformans [71].

9.1.4. Monoterpene Indole Alkaloids

Plants in the order Gentianales produce monoterpene indole alkaloids with moderate broad-spectrum antibacterial properties (Figure 1).

Strictosidine-typeindole alkaloid glycosides: The condensation of tryptophan and iridoid glycoside secologanin yields strictosidine, the precursor of 5α-carboxystrictosidine (Log D-3.1 at pH 7.4; molecular mass = 574.5 g/mol), which inhibited the growth of M. tuberculosis (H37Rv) with the MIC value of 26.3 µg/mL [72].

Iboga indole alkaloids: Iboga indole alkaloids are derived from strictosidine. Voacangine and ibogaine moderately inhibited the growth of M. tuberculosis and Mycobacterium kansasi [73]. 5-Oxocoronaridine and coronaridine were moderately active against repressed E. coli, B. subtilis, A. flavus, A. niger, and Rhizoctonia phaseoli [74]. The growth E. coli, K. pneumoniae, S. aureus, S. pneumoniae [74], A. flavus, C. albicans, and R. phaseoli was moderately inhibited by ibogamine [74]. Penicillium chrysogenum was moderately inhibited by 5-oxocoronaridine, 3-oxocoronaridine, and tabernamontamine [74].

Vobasine-type indole alkaloids: The growth of A. niger and A. flavus was moderately suppressed by vobasine [74]. Voacamine repressed R. phaseoli, P. chrysogenum, and C. albicans [74]. The growth was moderately hampered by vobasine [74].

Isomalindan-type indole alkaloids: Cadambine from Neolamarckia cadamba (Roxb.) Bosser (clade Lamiids) was weakly active toward Staphylococcus epidermidis, S. aureus, B. cereus, and B. subtilis, and C. albicans [75].

Corynanthe indole alkaloids: Strictosidine is the precursor to corynanthe indole alkaloids such as alstoniascholarine A, which hindered K. pneumoniae, Providencia smaitii, and E. coli with the MIC values of 12.5, 25, and 50 µg/mL, respectively [76] while alstoniascholarine E yielded the MIC values of 25, 25, and 25 µg/mL, against K. pneumoniae, P. smaitii, and E. coli with the MIC values of 100, 50, 50, respectively. Alstoniascholarine A and E moderately restrained M. gypseum, E. floccosum, and T. mentagrophytes [76]. Alstoniascholarine J repressed E. floccosum with the MIC of 31.2 µg/mL, and yielded the MICs of 3.1, 12.5, 12.5, 1.5, and 25 µg/mL with P. aeruginosa, E. faecalis, K. pneumoniae, P. smaitii, and E. coli, respectively [76]. Vallesamine and 5-hydroxy-19,20-Z-alschomine very strongly inhibited the growth of E. faecalis (ATCC 10541) and P. aeruginosa (ATCC 27853) with the MIC values of 1.5 and 0.7 µg/mL, respectively [77,78].

Strychnos-type indole alkaloids: Strictosidine is the precursor of Strychnos-type indole alkaloids such as tubotaiwine that moderately inhibited the growth of M. tuberculosis H37Rv (MIC: 100 µg/mL) [79].

9.1.5. Miscellaneous

The condensation of anthranilic acid with isatin yielded the indoloquinazoline alkaloid tryptanthrin, which very strongly inhibited MRSA (MIC: 0.5 μg/mL) and Malassezia furfur (MIC: 4 μg/mL) [34,80]. Tryptanthrin is a broad-spectrum antifungal alkaloid that yielded the MIC values of 3.1, 3.1, 3.1, 3.1, 6.3, and 3.1 µg/mL, against T. mentagrophytes, Trichophyton rubrum, Trichophyton tonsurans, Microsporum canis, M. gypseum, and E. floccosum respectively [81,82]. Tryptanthrin was strongly fungistatic with C. neoformans, and Cryptococcus deuterogattii (MIC/MFC: 2/>64 and 8/32 μg/mL) [83].

Plants in the genus Euodia from tryptophan via the condensation of dihydronorharman and N-methylanthranilic acid yield evodiamine with weak potencies against K. pneumoniae (MDR, clinical strain) [84]. Dehydroevodiamine (molecular mass = 301.3 g/mol) from the fruits of Euodia rutaecarpa Benth very strongly restrained X. oryxae pv oryzae (EC₅₀: 1.4 µg/mL) [61]

In the family Apocynaceae (clade Lamiids), the condensation of anthranilic acid with indoxyl yielded the indoloquinoline alkaloid cryptolepine, which repressed S. aureus (NCTC 10788), S. dysenteriae (ATCC 13313), V. cholerae (ATCC 11623), S. sclerotiorum, and Botrytis cinerea with the MIC values of 5, 6.2, <1.5, 5.5, and 0.05 µg/mL, respectively [7,18,85,86].

10. Piperidine Alkaloids

10.1. Piperine Alkaloids

Plants in the family Piperaceae (clade Magnoliids) convert L-lysine into piperidine, which combines with piperoyl-CoA to yield the strong broad-spectrum antibacterial piperine alkaloids (Figure 1). Piperine moderately impeded B. sphaericus (ATCC 14577), B. subtilis (ATCC 6051), E. coli (ATCC 25922), P. syringae (ATCC 13457), and S. typhimurium (ATCC 23564) and yielded a MIC of 3.9 µg/mL with S. aureus [47,87]. Piperine (200 µL of the 10 mg/mL/11 mm well) muzzled S. aureus, P. aeruginosa, and C. albicans [87]. Piperine is an antibiotic potentiator that inhibits mycobacterial efflux pumps [50,87]. Piperine very strongly constrained albicans [87] and at the concentration of 100 µg/mL suppressed R. solani, Fusarium gramineum, Alternaria tenuissima, Gloeosporium theae-sinensis, Phytophthora capsici, and Phomopsis adianticola by 63.1, 53, 66.1, 76.9, 41.8, and 29.3%, respectively [88]. Piperlongumine (200 µL of the 10 mg/mL/11 mm well) from Piper longum L. is active against S. aureus and P. aeruginosa increased the susceptibility of S. aureus to rifampicin [87] and very strongly inhibited C. albicans (MIC: 3.9 µg/mL) [87].

10.2. Quinolizidine Alkaloids

From L-lysine are produced quinolizidine alkaloids [89] in the Nymphaeaceae and Fabaceae (Figure 1). 6,6′-Dihydroxythiobinupharidine very strongly suppressed E. faecalis and Enterococcus faecium with the MIC ranging from 2 to 4 µg/mL and MRSA with a MIC of 2 µg/mL [90]. 7-Hydroxylupanineand N-butylcytisine from Sophora flavescens Aiton (clade Fabids) hindered S. aureus with the MIC values of 16 µg/mL [90] and N-butylcytisine yielded the MIC of 8 µg/mL with E. coli [90].

10.3. Phenanthroindolizidine Alkaloids

Plants in the family Lauraceae (clade Magnoliids), Moraceae (clade Fabids, and Asclepiadaceae (clade Lamiids) combine cinnamic acid and ornithine to yield strong broad-spectrum antifungal phenanthroindolizidine alkaloids [91] (Figure 1). One such alkaloid is tylophorinine, which suppressed C. albicans (14503), Candida krusei, Candida glabrata, and A. fumigatus with MIC values of 0.6, 0.6, 2.5, and 5 µg/mL, respectively [92]. Tylophorinidine yielded MIC values of 2, 4, 8, and 8 µg/mL with C. albicans (14503), C. krusei, C. glabrata, and A. fumigatus, respectively [92] (Table 1). 7-Demethoxytylophorine from Cynanchum atratum Bunge was very strongly antifungal with Penicillium italicum (MIC/MFC: 1.5/6.2 µg/mL) [25] and Penicillium digitatum (MIC/MFC: 1.5/12.5 µg/mL) [92].

10.4. Securinega Alkaloids

Plants in the family Phyllanthaceae (clade Fabids) produce Securinega alkaloids (Figure 1) such as viroallosecurinine, which is very active against P. aeruginosa and S. aureus (MIC: 0.4 μg/mL) [93]. Securinine weakly restrained P. aeruginosa, S. aureus, and M. smegmatis [93]. Allosecurinine and ent-seco norsecurinine inhibited the growth of a broad-spectrum of filamentous fungi [94,95].

10.5. Miscellaneous

Dihydrodioscorine (0.1% of agar) from Dioscorea bulbifera L. inhibited the mycelial growth and spore production of Sclerotium rolfsii, C. lunata, F. moniliforme, Botryodiplodia theobromae, and Macrophomina phaseolina [8]. Pandamarilactone-1 weakly restrained E. coli, P. aeruginosa, and S. aureus [96]. Among the Chenopodiaceae, haloxyline B moderately restrained M. tuberculosis H37Rv with the MIC of 50 µg/mL [97].

11. Quinoline Alkaloids

11.1. Simple Quinolines

From tryptophan via anthranilic acid with condensation with malonyl CoA plants in the clade Fabids yielded simple quinolines (Figure 1). 4-Methylquinoline hindered S. aureus (KCCM 11335) with the MIC/MBC values of 12.2/50 µg/mL [98]. Lunasia amara Blanco yielded 4-methoxy-2-phenylquinoline with MIC values of 16 µg/mL against M. tuberculosis H37Rv [98].

In the family Rutaceae (clade Malvids), the condensation of anthranilic acid with malonyl CoA followed by prenylation yielded antibacterial furanoquinolines such as dictamine from Dictamnus albus L. hindered Micrococcus luteus (TISTR 884) and B. cereus (TISTR 688) with the MIC values of 26 and 64 µg/mL, respectively [99,100] and was active against M. tuberculosis H37Rv [101]. γ-Fagarine and robustine are moderate broad-spectrum antibacterial furanoquinolines [100,101].

Members of the genus Gomphandra Wall. ex Lindl. are produced from the condensation of tryptamine and secologanin yields via strictodamide camptothecin, which is a strong broad-spectrum antifungal pyrrolquinoline alkaloid [102,103].

11.2. Benzylisoquinolines

In basal angiosperms (clade Magnoliids, Eudicots), the condensation of dopamine and p-hydroxyphenylacetaldehyde yielded strong broad-spectrum antibacterial and antifungal benzylisoquinoline alkaloids (Figure 1). One such alkaloid is reticuline [104,105]. From Fumaria indica Pugsley, fuyuziphine at a concentration of 500 ppm hindered the germination of spores of Alternaria brassicicola, A. solani, Alternaria melongenae, C. maculans, Erysiphe cichoracearum, and Helminthosporium pennisetti by more than 80% [106].

11.3. Bisbenzylisoquinolines

The radical coupling of benzylisoquinolines gives birth to antibacterial and antifungal bisbenzylisoquinoline alkaloids in plants in the clade Eudicots (Figure 1). For instance, the coupling of N-methyl coclaurine yields tetrandine, which is weakly bactericidal for S. aureus (ATCC 25923) and MRSA (ATCC 33591) [107] and is a bacterial efflux pump inhibitor [90,107].

Tiliacora triandra Diels produces tiliacorinine, 2′-nortiliacorinine, and tiliacorine, which achieved MIC values of 6.2, 3.1, and 3.1 µg/mL, respectively, toward M. tuberculosis (H37Rv) and MIC values ranging from 0.7 to 6.2 µg/mL against several clinical isolates of multidrug-resistant M. tuberculosis [108]. Tiliacorine inhibited the germination of the conidia of A. tenuissima by more than 60% at 100 µg/mL [109].

11.4. Aporphines

The cyclization by oxidative coupling of benzylisoquinolines yields aporphines in basal angiosperms. For instance, in Figure 1, liriodenine [110] inhibited a very broad spectrum of bacteria and phytopathogenic fungi [111] as well as Histoplasma capsulatum (MIC: 1.9 μg/mL) [28].

Anonaine developed halos against B. cereus (ATCC-14.579), E. coli (ATCC-11.105), S. aureus (ATCC-6538), and S. epidermidis (ATCC-12.228) with diameters of 20, 8, 14, and 12 mm, respectively (1 mg/mL, 70 µL/well) [84]. In a subsequent study, anonaine weakly inhibited the growth of S. mutans (ATCC 25175) (Lall et al., 2017), T. rubrum, and M. gypseum [85].

Lysicamine was moderately active with S. epidermidis (MIC: 50 µg/mL) [112], and very strongly repressed L. monocytogenes, MSSA, S. pneumoniae, and Actinobacillus sp. with the MIC values of 2.5, 1, 4, and 2.5 µg/mL, respectively, and K. pneumoniae (ESBL)with the MIC of 20 µg/mL [113]. Lysicamine (10 µg/6 mm disk) developed inhibition zone diameters of 12, 13, and 15.5 mm toward S. epidermidis, S. aureus, and B. subtilis, respectively [113], and had meek effects with Candida dubliniensis (ATCC 777) [33].

O-methylmoschatoline (200 µg/disk) inhibited the growth of S. aureus, E. coli, P. aeruginosa, S. typhi, and K. pneumoniae with zone diameters of 20, 12, 12, 20, and 22 mm, respectively [114]. Xylopine hindered B. cereus, Micrococcus sp., and S. aureus [115] as well as V. cholerae, E. coli, and S. dysenteriae [116]. Artabotrine was very strongly bactericidal against K. pneumoniae (ESBL) (MIC/MBC: 2.5/2.5 μg/mL) [113]. The azaoxoaporphine sampangine (Log D 2.7 at pH 7.4; molecular weight 232.2 g/mol) was very strongly active with C. albicans (ATCC 90028), C. glabrata (ATCC 90030), C. kruseii (ATCC 6258), A. fumigatus (ATCC 90906), and C. neoformans (ATCC 90113) with MIC values of 3.1, 3.1, 6.2, 6.2, and 0.05 µg/mL, respectively [117] and at 10 µg/disk developed halos with B. cereus, S. aureus, E. coli, and S. typhi [118]. Lanuginosine (10 µg/disk) invoked inhibition zone diameters of 12, 14, 10, 14, and 12 mm, with halos with B. cereus, S. aureus, E. coli, K. pneumoniae, and P. aeruginosa, respectively [118].

Nordicentrine (Log D 3.0 at pH 7.4; molecular weight = 325.3 g/mol) suppressed M. tuberculosis with a MIC of 12.5 µg/mL [119] as well as Cladosporium clodosporioides (6 µg/spot) [120]. Dicentrinone was moderately antimycobacterial [121].

The oxoaporphine thailandine restrained S. pneumoniae, S. aureus, and E. faecalis with MIC values of 30, 30, and 60 µg/mL, respectively, and yielded an IC₅₀ value of 6.2 µg/mL with M. tuberculosis (H₃₇Ra) [122].

Isoboldine was moderately active with E. coli, P. aeruginosa, P. mirabilis, K. pneumoniae, A. baumanii, S. aureus, B. subtilis [104], and C. albicans [123]. Bulbocapnine restrained K. pneumoniae and A. baumanii with the MIC values of 32, 64, 32, 8, 8, 64, and 128 µg/mL respectively [104].

Roemerine is a moderate inhibitor of MRSA (135), S. aureus (ATCC25913) C. albicans (SC 5314), C. glabrata (8535), C. krusei (4996), Candida tropicalis (8915), Candida parapsilosis (90018), and A. fumigatus (7544), respectively [124] and yielded a MIC value of 10 μg/mL with C. albicans (ATCC 90028) [125].

Magnoflorine moderately repressed C. albicans (KCTC7965), C. albicans (KACC30071), C. parapsilosis var. parapsilosis (KACC45480), T. rubrum, and T. mentagrophytes [126,127].

11.5. Protopines

Benzylisoquinolines are precursors of protopine that restrained E. coli, P. aeruginosa, P. mirabilis, K. pneumoniae, A. baumanii, S. aureus, and B. subtilis with the MIC values of 32, 64, 32, 8, 8, 64, and 128 µg/mL, respectively [104] as well as Streptococcus agalactiae [128]. Protopine inhibited the growth of C. albicans with the MIC value of 4 µg/mL [104]. Allocryptopine was weakly active with S. aureus, P. aeruginosa, E. coli, and S. agalactiae [128].

11.6. Protoberberines

The cyclization of benzylisoquinolines yielded very strong antibacterial protoberberines such as in pendulamine A from Polyalthia longifolia (Sonn.) Thwaites that yielded the MIC of 2, 0.02, 0.2, 0.02, 2, 2, 0.2, and 0.02 µg/mL against B. subtilis, Corynebacterium hoffmanii, S. aureus, Micrococcus lysodickycus, K. pneumoniae, P. aeruginosa, S. typhi, and S. paratyphi A, respectively [129]. Pendulamine B restrained Corynebacterium hoffmanii, S. aureus, S. faecalis, S. viridans, M. lysodickycus, K. pneumoniae, P. aeruginosa, S. typhi, and S. paratyphi A with the MIC values of 0.02, 0.2, 2, 0.02, 0.02, 2, 0.2, and 0.2 µg/mL, respectively [129].

11.7. Spirobenzylisoquinolines

Spirobenzylisoquinolines are derived from benzylisoquinolines via protoberberine. and include (+)-parfumine, fumarophycine and (+)-fumariline (that moderately restrained E. coli, P. aeruginosa, P. mirabilis, K. pneumoniae, A. baumanii, S. aureus, and B. subtilis [104].

11.8. Benzophenanthridines

Plants in the clade Eudicots use reticuline as a precursor of benzophenanthridines such as stylopine or sanguinarine L. that moderately repressed E. coli, P. aeruginosa, P. mirabilis, K. pneumoniae, A. baumanii, S. aureus, and B. Subtilis [104]. Dihydrosanguinarine was a weak repressor of E. coli [128]. Sanguinarine impeded S. mutans (ATCC 25175) with the MIC value of 32 µg/mL [130] as well as S. aureus, P. aeruginosa, E. coli, and S. agalactiae with MIC values of 31.3, 250, 62.5, 15.6 µg/mL, respectively [128]. 6-Methoxydihydrosanguinarine (10 µg/disk) developed an inhibition zone diameter of about 17 mm with S. aureus and MRSA [131]. 8-Hydroxydihydrosanguinarine (molecular weight = 349.3 g/mol) inhibited the growth of clinical strains of MRSA with MIC ranging from 0.4 to 7.8 µg/mL and MBC ranging from 1.9 to 31.2 µg/mL, ESBL strains of E. coli with MIC ranging from 15.6 to 250 µg/mL and MBC ranging from 62.5 to 500 µg/mL, and E. coli with MIC of 15.6 µg/mL and MBC of 31.2 µg/mL [109]. 8-Hydroxydihydrosanguinarine was moderately active against C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, and C. neoformans [132].

6-Methoxydihydrosanguinarine is a very strong inhibitor of E. faecalis and S. aureus (ATCC 25925) with the MIC/MBC of 5/10, 2.5/5 µg/mL, respectively, and evoked milder potencies with E. coli (ATCC 25922) [133] and C. albicans (CMCC 85021) [133]. Norsanguinarine is moderately antibacterial [104].

Allocryptopine is the precursor of dihydrochelerythrine that strongly hindered S. epidermidis (ATCC 12228), S. aureus (ATCC 6538), S. pyogenes (ATCC 19615), B. subtilis (ATCC 6633), K. pneumoniae (ATCC 13883), and E. coli (ATCC 25922) with MIC/MBC values of 6.2/12.5, 12.5/50, 12.5/50, 25/50, 12.5/25, 25/25 µg/mL, respectively [134]. 8-Hydroxydihydrochelerythrine (molecular weight = 365.4 g/mol) inhibited the growth of 20 strains of MRSA clinical isolated with MIC ranging from 0.9 to 15.6 µg/mL and MBC ranging from 7.8 to 62.5 µg/mL [135] and displayed meeker effects with E. coli and K. pneumoniae (ESBL) [109,135]. Dihydrochelerythrine suppressed MRSA (SK1) and E. coli (TISTR 780) with the MIC values of 8 and 16, and 128 µg/mL [100]. Dihydrochelerythrine is the precursor of chelerythrine, which very strongly hindered S. epidermidis (ATCC 12228), S. aureus (ATCC 6538), S. pyogenes (ATCC 19615), B. subtilis (ATCC 6633), K. pneumoniae (ATCC 13883), and E. coli (ATCC 25922) with MIC/MBC values of 1.5/12.5, 1.5/3.1, 1.5/6.2, 1.5/50, 1.5/50, and 1.5/25 µg/mL, respectively [128,134]. Chelerythrine was also very strongly antifungal with C. albicans (ATCC 10231), S. cerevisae (ATCC 2601), and C. neoformans (ATCC 28952) with MIC/MBC values of 3.1/3.1, 6.2/6.2, and 3.1/6.2 µg/mL, respectively [134,136]. Corynoline and acetylcorynoline from Corydalis incisa (Thunb.) Pers. evoked inhibitory halos with Cladosporium herbarum (3 µg/spot) [137].

Norchelerythrine inhibited the growth of M. tuberculosis with the MIC value of 25 µg/mL [138]. Avicine very strongly suppressed S. epidermidis (ATCC 12228), S. aureus (ATCC 6538), S. pyogenes (ATCC 19615), B. subtilis (ATCC 6633), K. pneumoniae (ATCC 13883), and E. coli (ATCC 25922) with the MIC/MBC values of 3.1/12.5, 1.5/25, 1.5/12.5, 1.5/6.2, and 6.2/12.5 µg/mL, respectively [134]. 8-Acetylnorchelerythrine yielded the MIC values of 1 µg/mL with S. epidermidis, E. coli, E. cloacae, K. pneumoniae, and P. aeruginosa [139]. Rhoifoline B moderately inhibited the growth of S. aureus, S. epidermidis, E. coli, E. cloacae, K. pneumoniae, P. aeruginosa, and S. dysenteriae [139]. Nitidine, from a member of the genus Zanthoxylum L. (clade Malvids), weakly inhibited the growth of M. luteus, S. aureus, and M. smegmatis [140].

11.9. Protoberberines

Reticuline is precursor of the broad-spectrum antibacterial berberine [29,128,141,142,143,144]. Of note, berberine curbed the growth of K. pneumonia and A. baumanii with the MIC value of 8 µg/mL [104] and Neisseria gonorrhea with the MIC of 13.5 µg/mL [145]. Berberine decreased the MICs of ampicillin and oxacillin against MRSA and evoked a synergistic effect [146] and impeded the MexAB antibiotic efflux pump in P. aeruginosa [147]. Berberine suppressed fluconazole-resistant clinical strains of C. tropicalis, C. albicans, C. parapsilosis, and C. neoformans as well as C. krusei (ATCC 6258) and C. parapsilosis (ATCC 22019) with the MIC values of 8, 8, 8, 8, 8, 8, 8, 16, 16, 16, 16, 4, and 16 µg/mL, respectively [148] and at a concentration of 500 ppm blocked the germination of spores of Curvularia lunata, Erysiphe cichoracearum, F. udum, and Penicillium sp. by more than 80% [106]. Berberine at the concentration of 1.9 µg/mL decreased the MIC of fluconazole from 1.9 to 0.4 µg/mL [149] and inhibited the growth of M. smegmatis (ATCC 607) with the MIC value of 25 µg/mL [150].

Berberine is a precursor of jatrorrhizine that curbed strains of P. acnes with MIC between 5 and 50 µg/mL, [143]. In a subsequent study, jatrorrhizine weakly inhibited S. aureus, B. subtilis, E. coli, and S. dysenteriae [151] as well as the clinical isolates of E. floccosum, T. rubrum, Trichophyton interdigitale, Trichophyton violaceum, T. mentagrophytes, T. equinum, M. canis, M. gypseum, C. albicans, and C. tropicalis [152]. Palmatine t is moderately antibacterial as well as a sinactine [104] and MexAB antibiotic efflux pump blocker in P. aeruginosa [147].

11.10. Phthalides

Protoberberine alkaloids are precursors of phthalides with moderate antibacterial potencies including adlumidine or bicuculline [104]. Bicuculline at 200 ppm restrained the spore germination of A. brassicae, Curvularia lanata, and F. udum [104,153].

11.11. Hasubanans

Within the family Menispermaceae, intramolecular coupling of benzylisoquinolines form hasubanan alkaloids. One such alkaloid is glabradine, isolated from the tubers of Stephania glabra (Roxb.) Miers, which suppressed S. aureus and S. mutans with the MIC value of 50 µg/mL as well as M. gypseum, M. canis, and T. rubrum with the MIC values of 25, 25, and 50 µg/mL, respectively [154].

11.12. Amaryllidaceae Alkaloids

Plants in the family Amaryllidaceae (clade Monocots) condensate protocatechuic aldehyde and tyramine to yield antibacterial Amaryllidaceae alkaloids such as crinamine [9]. Other examples are lycorine and lycoricidine (1 mg/mL/8 mm disk), which developed an inhibition zone of 13 and 12 mm with E. coli, respectively [106]. Lycorine at the concentration of 100 µg/mL hindered Alternaria oleracea, C. gloeosporioides, F. graminearum, Colletotrichum ophiopogonis, and Pleospora lycopersici by 61.9, 57.2, 63.7, 63.2, and 52.6%, respectively [155]. Lycorine yielded the MIC values of 39, 32, 512, 64, and 97.3 µg/mL with C. albicans, Candida dubium, C. glabrata, Lodderomyces elongisporus, and S. cerevisae, respectively [156]. Narciclasine inhibited the growth of Corynebacterium fascians and C. neoformans [157] and hippeastrine moderately curbed C. albicans [156]. Tazettine from Narcissus tazetta L. weakly restrained C. dubliniensis and L. elongisporus [156].

11.13. Miscellaneous

11.13.1. Quinolinones

Plants in the clade Malvids yield antibacterial and antifungal quinolinones. Antidesmone at the concentration of 50 µg/mL restrained Botryosphaeria dothidea, Colletotrichum musae, Pestalotipsis guepinii, Colletotrichum orbiculare, Phylophthora nicotianae, Pestalotiopsis longiseta, Carbendazim-sensitive strains of S. sclerotiorum, and Carbendazim-resistant strains of S. sclerotiorum by 71.9, 84.6, 86.7, 75.5, 78.8, 83.4, 56.5, and 100%, respectively [158]. Waltherione C at the concentration of 50 µg/mL inhibited B. dothidea, Colletotrichum musae, Pestalotipsis guepinii, Colletotrichum orbiculare, Phylophthora nicotianae, Pestalotiopsis longiseta, carbendazim-sensitive strains of S. sclerotiorum, and carbendazim-resistant strains of S. sclerotiorum by 60, 43, 71.4, 60.9, 41.6, 3.6, 79.8, and 81.8%, respectively [158].

Members of the genus Euodia J.R. Forst. & G. Forst. bring to being series of antibacterial (Gram-positive) long chain quinolinones born of the condensation of anthranilic acid, malonyl-CoA and fatty acyl-CoA (also produced by Gram-negative bacteria). 1-Methyl-2-nonyl-4(1H)-quinolone very strongly repressed S. aureus (ATCC 25393), S. epidermidis (ATCC 12228), and B. subtilis (ATCC 6633) with the MIC values of 4, 4, and 8 µg/mL, respectively [159]. 1-Methyl-2-[(Z)-5′-pentadecenyl]-4(1H)-quinolone isolated from the fruits hindered S. aureus (ATCC 25393), S. epidermidis (ATCC 12228), and B. subtilis (ATCC 6633) with the MIC values of 16, 4, and 16 µg/mL, respectively [159]. In a subsequent study, the lipophilic long chain quinolinone alkaloid evocarpine inhibited the growth of MRSA (ATCC 33591) and S. aureus (ATCC 25923) with the MIC values of 8 and 8 µg/mL, respectively [160] and very strongly suppressed M. fortuitum (ATCC 6841), M. smegmatis (ATCC 19429), and M. phlei (ATCC 19249) with the MIC values of 2, 2, and 2 µg/mL, respectively [161].

11.13.2. Acridanones

In the family Rutaceae (clade Malvids), the condensation of anthranilate with 3 malonyl CoA yielded acridanones such as 1-hydroxy-3,4-dimethoxy-10-methylacridan-9-one [162] or 1-hydroxy-3-methoxy-10-methyl-acridan-9-one that repressed E. coli [69] (Table 1).

11.13.3. Phenanthrene Alkaloids

Benzylisoquinolines are precursors of antibacterial phenanthrene in basal clades as aristolochic acid, which inhibited the growth of Moraxella catarrhalis (GTC 01544) with MIC/MBC values of 25/50 µg/mL [163] as well as B. subtilis and E. coli [164], P. aeruginosa, S. faecalis, S. aureus, and Staphylococcus epidermidis [165]. Another example is aristolactam N-(6′-trans-p-coumaroyl)-β-d-glucopuyranoside, which restrained B. subtilis and S. lutea with the MIC values of 43.8 and 175 µg/mL, respectively [166]. These phenanthrene alkaloids bind covalently with DNA [167,168]. 1-N-monomethylcarbamate-argentinine-3-O-β-d-glucoside at 500 µg/disk hindered MRSA with an inhibition zone diameter of 8 mm [169].

12. Pyrrolidines and Imidazole Alkaloids

In the family Piperaceae (clade Magnoliids), the pyrrolidines brachyamide B yielded the IC₅₀ of 41.8 µg/mL against a clinical isolate of C. albicans [170] and suppressed C. neoformans (ATCC 90 113) with an IC₅₀ of 7.1 µg/mL [171]. Other instances are trachyone and isopiperolein B with S. aureus (MIC of 30 and 36 µM, respectively) [51]. The pyrrolidine alkaloid lactone pandamarilactonine A moderately inhibited the growth of E. coli, P. aeruginosa, and S. aureus [96]. The pyrrolidine amide N-[9-(3,4-Methylenedioxyphenyl)-2E,4E,8E-nonatrienoyl] pyrrolidine was active toward M. tuberculosis (H37Ra MIC: 25 µg/mL) [170].

The imidazole alkaloid allantoin very strongly hindered B. subtilis with the MIC value of 4 µg/mL as well as S. aureus, E. coli, and K. pneumoniae with the MIC value of 8, 8, and 8 µg/mL, respectively [172] (Table 1).

13. Diterpene Alkaloids

Plants in the family Ranunculaceae (clade Eudicots) produce a unique type of moderately antifungal diterpene alkaloids. For instance, 8-acetylheterophyllisine, vilmorrianone, and panicutine inhibited the growth of Allescheria boydii, A. niger, E. floccosum, and Pleurotus ostreatus [173] (Table 1).

14. Steroidal Alkaloids

N-formylconessimine and conimine suppressed MSSA and MRSA with MIC values of 32 and 128 μg/mL, respectively, and conimine increased the sensitivity of MSSA to vancomycin [174].

15. Concluding Remarks

Weinstein and Albersheim (1983) presented evidence that phytoalexins, especially flavonoids from angiosperms, act as nonspecific membrane antimicrobials that alter the structural integrity of the cytoplasmic membrane, thereby causing the membrane to be a less efficient matrix for membrane-dependent processes [175]. They also argue that phytoalexins with non-specific antimicrobial targets targeting the cytoplasm and proteins also makes it difficult for bacteria or fungi to develop resistance. Furthermore, phytoalexins are often toxic to herbivorous predators as well as repellent and therefrom exhibit low therapeutic indices. In the case of alkaloids, none have been known act on specific antibacterial or antifungal targets [176]. It is for this reason that antibiotic or antifungal alkaloids for systemic use in humans working at micromolar plasmatic concentrations have not been found yet. Research efforts, however, need to continue with the determination of the selectivity indices. Alkaloids from Asian angiosperms represent yet another mind-blowing source of original chemical frameworks that can be used for the hemisynthesis of clinical antibiotics, antimycobacterial agents, and antifungal drugs as well as efflux pump inhibitors of clinical value. 8-Acetylnorchelerythrine, cryptolepine, 8-hydroxydihydrochelerythrine, 6-methoxydihydrosanguinarine, 2′-nortiliacorinine, pendulamine A and B, rhetsisine, sampangine, tiliacorine, tryptanthrin, tylophorinine, vallesamine, and viroallosecurinine with a MIC ≤1 µg/mL are first line candidates.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/antibiotics11091146/s1, Table S1: Medicinal Plants of Asia and the Pacific yielding antibacterial and/or antifungal alkaloids; Table S2: Antibacterial and/or antifungal alkaloid in vitro and from Asian Angiosperms with MIC ≤ 5 µg/mL.

Author Contributions

Conceptualization, C.W.; Methodology, M.S. (Mazdida Sulaiman) and J.-F.W.; Formal analysis, M.S.B. and M.K.B.B.; Investigation, C.W.; Resources, C.W.; Data curation, A.K.P.; Writing—original draft preparation, C.W.; Writing—review and editing, K.J., V.N., M.R. (Mogana Rajagopal), A.K.P., M.d.L.P., M.S. (Mazdida Sulaiman), M.S. (Monica Suleiman) and M.R. (Mohammed Rahmatullah); Visualization, P.W.; Supervision, C.W.; Project administration, C.W.; Funding acquisition, C.W. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Funding Statement

This project was funded by a grant from the Malaysian Ministry of Education (FRGS/1/2018/ WAB07/UNIM/02/1, Malaysian Ministry of Higher Education, Malaysia) and Project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MEC (PIDDAC).