Phytochemical interventions in bacterial resistance: plant metabolites as next-generation antibacterial agents

1 Introduction

Antibiotic resistance has become much more common in microorganisms over the past 10 years, especially in Gram-negative bacteria. Due in large part to the extensive use of antibacterial agents for treatment and MDR and XDR bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococcus (VRE), Escherichia coli (E. coli), Pseudomonas aeruginosa, and others, have also been identified, particularly in hospital settings (Stan et al., 2021; Porras et al., 2020).

People have used plants and other natural sources, including bacteria, fungi, marine organisms, and animals, to treat and prevent infectious diseases (caused by bacteria, viruses, and protozoa) and other ailments like cancer, inflammation, and Alzheimer’s disease since ancient times. When taken improperly or in excess, these natural medicines have ranged from curing symptoms or curing diseases to, in certain situations, causing serious poisoning (Stan et al., 2021; Ciocan and Bara, 2016; Thawabteh et al., 2024a; 2025).

Given that plants have long been known to have therapeutic benefits, phytochemistry presents encouraging alternatives. The market for natural products expanded dramatically between 2015 and 2025, bringing in between 29.4 and 39.6 million dollars, which is indicative of their growing demand and use. The secondary metabolites found in natural products, including tannins, phenols, xanthones, flavonoids, terpenoids, coumarins, thiophenes, naphthoquinones, and alkaloids, are responsible for these medicinal effects. In plants, these metabolites have a variety of functions. Tannins and quinones contribute coloring pigments, terpenoids give plants their unique scents, and other compounds are created as defense mechanisms against pathogens, such as bacterial infections (Stan et al., 2021; Ciocan and Bara, 2016; Thawabteh et al., 2025; Moloney, 2016).

Many of the antibiotics that are currently on the market, including azoles, macrolides, penicillins, and tetracyclines, are extracted or derived from natural sources. To combat the escalating problems of antibiotic resistance, novel sources and substances have been studied more and more in recent years. Many of the roughly 250,000–500,000 plant species that exist on Earth have been used medicinally (Stan et al., 2021; Thawabteh et al., 2024a; 2025).

In order to address bacterial resistance and investigate the potential of natural products as efficient substitutes to fight the growing crisis of bacterial resistance in both Gram-positive and Gram-negative pathogens, the review attempts to offer a thorough framework for comprehending the role of natural products derived from alkaloids, terpenoids, phenolics, saponins, polyketides, lignans, fatty acids, lipids, peptides, terpenes, steroids, carbohydrates, and essential oils.

This review is also intended to provide a structured preliminary reference resource for researchers investigating plant-derived antibacterial candidates against MDR and XDR pathogens. By organizing phytochemicals according to their chemical classes, bacterial targets, MIC values, mechanisms of action, and reported synergistic interactions with conventional antibiotics, the manuscript aims to facilitate comparative assessment and support future prioritization of promising natural metabolites for antibacterial drug discovery.

The novelty of this review lies not only in the broad compilation of plant-derived antibacterial metabolites, but also in the comparative organization of these compounds according to chemical class, antibacterial spectrum, MIC potency, resistance-related mechanisms, and reported synergy with conventional antibiotics. Unlike narrative reviews that primarily summarize plant extracts or isolated compounds, this review aims to provide a mechanistically oriented framework that links phytochemical diversity with antibacterial performance against clinically relevant MDR and XDR pathogens. This approach allows the identification of compound classes with stronger translational potential, while also highlighting recurring limitations in the current literature, including inconsistent MIC reporting, limited in vivo validation, variable extract standardization, and insufficient pharmacokinetic and toxicity data.

2 Mechanisms of antibiotic resistance

When bacteria develop defences against the effects of drugs intended to eradicate them, antibiotic resistance—a rising public health concern—occurs. This issue presents serious difficulties for healthcare systems around the world and makes treating infections more difficult. To effectively address this problem and maintain the effectiveness of currently available medicines, it is imperative to comprehend the mechanisms underlying antibiotic resistance (Aslam et al., 2018; Uddin et al., 2021; Muteeb et al., 2023).

2.1 Gram-positive bacteria

The thick peptidoglycan coating that identifies Gram-positive bacteria offers structural stability and defense against environmental stresses. Their capacity to hold onto the crystal violet stain during the Gram staining procedure, which gives them a purple colour under a microscope, is due to this thick coating. Notable pathogens like MRSA and Streptococcus pneumoniae are included in this group. Many Gram-positive bacteria have teichoic acids in addition to peptidoglycan, which are involved in cell wall maintenance and cell division regulation (Rajagopal and Walker, 2015; Kleanthous and Armitage, 2015).

Six genera of Gram-positive bacteria are widely recognized as significant human pathogens. Morphologically, these genera are predominantly rod-shaped, with the exception of Streptococcus and Staphylococcus, which are spherical. These rod-shaped organisms are further categorized by their ability to produce spores; while Bacillus and Clostridium are characterized as spore-formers, Corynebacterium and Listeria-a coccobacillus-do not generate spores. Among the spore-producing taxa, classification is based on oxygen requirements, as Bacillus species are facultative anaerobes, whereas Clostridium species are obligate anaerobes. Beyond human pathogens, certain Gram-positive taxa, such as Rathayibacter, Leifsonia, and Clavibacter, are primarily associated with plant diseases (Cabrol et al., 2021; Sizar et al., 2017).

Notably, newborns can have serious infections from Gram-positive bacteria that could be fatal. Catabacter hongkongensis is an emerging pathogen that belongs to the Bacillota phylum and is one of the more recent clinically relevant Gram-positive species (Liu et al., 2021b; Cabrol et al., 2021; Sizar et al., 2017). However, MRSA and VRE are well known for being resistant to several medicines, which makes treatment choices more difficult and raises the rates of morbidity and death linked to infections brought on by these organisms (Sizar et al., 2017; Rödenbeck et al., 2023).

2.1.1 Mechanisms of resistance

As illustrated in Figure 1, Gram-positive bacteria use a variety of defense mechanisms against the effects of antibiotics. Target site change is one of their main tactics. For example, penicillin-binding proteins (PBPs), which are necessary for cell wall formation, are bound by β-lactam antibiotics to produce their effects. Certain Gram-positive bacteria can change their PBPs in response to β-lactam exposure either by acquiring new genes that encode modified PBPs with a lower affinity for β-lactams or by undergoing genetic changes. This process has been observed in S. aureus strains that have acquired the mecA gene, which codes for a new PBP that is less sensitive to β-lactam antibiotics, and so evolved methicillin resistance (Jubeh et al., 2020). The enzymatic breakdown of antibiotics is another important mechanism.

The β-lactamases, which are enzymes that can hydrolyze the β-lactam ring structure and make the antibiotic useless, are produced by certain Gram-positive bacteria. Although Gram-negative bacteria are more likely to have this mechanism, certain Gram-positive organisms have also acquired it. For instance, it has been demonstrated that Enterococcus faecium produces enzymes that provide resistance to ampicillin and other β-lactam antibiotics (Rajput et al., 2024). Treatment options are severely hampered by the introduction of such resistant pathogens (Rajput et al., 2024).

Gram-positive bacteria have the ability to create physical barriers that hinder the effectiveness of antibiotics in addition to altering target sites and generating degrading enzymes. The thickening of the cell wall is one such tactic. Vancomycin exposure, for example, has been shown to cause Staphylococcus aureus to build a thicker cell wall, which prevents the antibiotic from penetrating the cell (Reygaert, 2018). Because of this adaptability, the bacteria can live in settings that include antibiotics. Furthermore, a large number of Gram-positive bacteria have the ability to create biofilms, which are organized groups of bacteria encased in extracellular matrix that they produce on their own (Reygaert, 2018).

The protected environment that biofilms offer improves bacterial viability and fuels antibiotic resistance. Because of decreased medication penetration and changed metabolic states within the biofilm population, bacteria in biofilms are frequently less amenable to antibiotic therapy. Because biofilm formation can result in persistent infections that are challenging to eliminate, this phenomenon is especially problematic in cases of chronic illnesses (Munita and Arias, 2016).

2.2 Gram-negative bacteria

Gram-negative bacteria are distinguished by the composition of their cell envelope, which is made up of an inner membrane, a thin peptidoglycan layer, and an outside membrane. Lipopolysaccharides (LPS), which are found on the outer membrane, are essential for the pathogenicity and immune evasion of bacteria. Strong immunological reactions in hosts can be triggered by LPS, and in extreme situations, this can result in septic shock and inflammation (Caroff and Novikov, 2020). When counterstained with safranin, the thin peptidoglycan layer, which offers structural support, is unable to hold the crystal violet stain during the Gram staining procedure, giving the sample a pink or red hue (Caroff and Novikov, 2020).

Additionally, Gram-negative bacteria are renowned for their adaptability and versatility. They can flourish in a variety of settings, including the human body, soil, and water. Their capacity to create biofilms—communities of bacteria that stick to surfaces and are covered in a protective matrix—is one factor contributing to their flexibility. Biofilms can contribute to chronic illnesses and increase bacterial survival in harsh environments (Zhao et al., 2023).

Based on their phenotypic and genetic traits, Gram-negative bacteria are divided into a number of categories. Enterobacteriaceae and non-fermenters are the two main groups. Salmonella and E. coli are two well-known pathogens that belong to the Enterobacteriaceae family and are frequently linked to gastrointestinal diseases. Acinetobacter baumannii and Pseudomonas aeruginosa are two examples of non-fermenters that are commonly linked to hospital-acquired infections, especially in patients with impaired immune systems (Gniadek et al., 2016; Dweib et al., 2015; Oliveira and Reygaert, 2025). Many species within these groupings show different levels of antibiotic resistance and pathogenicity.

For example, whereas some strains of E. coli may be benign commensals in the stomach, others may cause severe diarrhoea or UTIs. Similar to this, P. aeruginosa is infamous for being resistant to several antibiotics and frequently causes infections in patients undergoing invasive procedures or those with cystic fibrosis (Sora et al., 2021; Malhotra et al., 2019).

2.2.1 Mechanisms of resistance

As seen in Figure 1, the high degree of antibiotic resistance exhibited by Gram-negative bacteria is one of the most urgent issues. Because of their distinct cell wall construction, many species have innate resistance mechanisms that restrict the ability of antibiotics to penetrate. Therefore, Gram-negative bacteria’s outer membrane is essential to their resistance to a variety of antibiotics, such as β-lactams, quinolones, colistins, and others. Most antibiotics need to pass through this outer barrier in order to get to their intended targets (Maher and Hassan, 2023; Miller, 2016).

While hydrophilic antibiotics, like β-lactams, enter through porins, hydrophobic medicines usually use a mechanism of diffusion to get past this barrier. Vancomycin, on the other hand, cannot employ these pathways due to its structure, which stops it from penetrating the outer membrane. Increased resistance may result from any alterations Gram-negative bacteria make to their outer membrane, such as mutations in porins or adjustments to their hydrophobic properties. Gram-negative bacteria have a higher level of antibiotic resistance than their Gram-positive counterparts because Gram-positive bacteria lack this crucial layer (Maher and Hassan, 2023; Miller, 2016; Sun et al., 2021). Along with a number of non-enzymatic processes, the synthesis of enzymes that deactivate antibiotics can also contribute to antimicrobial resistance in Gram-negative bacteria. Chromosome gene abnormalities may be the cause of this resistance. These mutations might increase intrinsic resistance by means of processes such altered permeability, improved efflux pumps, increased expression of enzymes that deactivate antibiotics, or changes to target locations (Gauba and Rahman, 2023). Furthermore, transportable genetic elements, such as plasmids encoding β-lactamases and enzymes that alter aminoglycosides, can be transferred to gain resistance (Gauba and Rahman, 2023).

Fluoroquinolone resistance in Enterobacteriaceae is also a result of non-enzymatic tactics, such as the quinolone resistance gene (Qnr), which confers quinolone resistance and is found on plasmids (Gauba and Rahman, 2023; Connelly et al., 2016; Jacoby et al., 2015; Nelson et al., 2021). Treating infections brought on by Gram-negative bacteria has become extremely difficult as a result of the advent of MDR strains. Higher rates of morbidity and mortality, longer hospital admissions, and higher healthcare expenses are frequently the outcomes of infections brought on by these organisms (Tsachouridou et al., 2023; Barrasa-Villar et al., 2017).

2.3 Challenges in treatment

Clinical medicine faces many difficulties as a result of the rise of MDR and XDR bacterial strains. Healthcare professionals are facing an increasing challenge in treating illnesses that were previously easily treatable as these germs develop more resistant to traditional treatments. Addressing the difficulties presented by MDR and XDR strains of bacteria requires an understanding of the mechanisms by which resistance is developed (Barlow, 2018; Parmanik et al., 2022). Clinicians’ options for therapy have been drastically reduced by the emergence of MDR and XDR strains. The use of last-resort drugs, which frequently have serious side effects and are more expensive, may become necessary when traditional antibiotics are no longer effective (Barlow, 2018; Parmanik et al., 2022).

Combination therapy, which uses many antibiotics to maximize efficacy, may be used in some situations by medical professionals; however, this strategy may be complicated by possible medication interactions and elevated toxicity (Parmanik et al., 2022). In addition to having fewer antibiotic alternatives, treating infections brought on by MDR and XDR strains frequently calls for a more customized strategy. When creating a treatment plan, clinicians need to take into account the patient’s general health status, the site of infection, and the particular pathogen involved. Delays in adequate therapy due to this intricacy may affect patient outcomes (Horcajada et al., 2019). Treatment efforts may also become more difficult if resistant strains are not promptly identified due to a lack of quick diagnostic techniques (Horcajada et al., 2019; Park et al., 2019).

A diversified, multifaceted strategy is essential to address the formidable challenges presented by MDR and XDR strains. Beyond the development of traditional antimicrobial agents, innovative approaches now prioritize mechanisms that bypass conventional resistance pathways. These include antivirulence strategies, which aim to disarm pathogens by targeting toxin production or quorum sensing without imposing strong selective pressure on bacterial survival. Furthermore, physicochemical strategies, such as the use of nanomaterials or photodynamic therapy, offer promising means to physically disrupt bacterial structures. The integration of monoclonal antibodies and biological alternatives, including bacteriophage therapy and antimicrobial peptides, further expands the therapeutic arsenal against resistant infections (Horcajada et al., 2019; Catalano et al., 2022). Complementing these clinical interventions, robust antibiotic stewardship remains critical; by promoting the judicious use of antimicrobials in both clinical and agricultural settings, the selective pressure on bacterial populations can be significantly mitigated (Catalano et al., 2022).

Promoting appropriate antibiotic usage can be greatly aided by patient and healthcare provider education and awareness initiatives. Lastly, it is critical to improve infection prevention strategies in healthcare environments. This entails rigorous adherence to hygienic guidelines, efficient sterilizing methods, and strong surveillance systems to quickly identify and contain outbreaks. Healthcare systems can more effectively handle the difficulties presented by MDR and XDR strains by putting these tactics into practice jointly (Ciocan and Bara, 2016; Park et al., 2019).

3 Antibacterial compounds derived from natural sources

Given the growing issue of antibiotic resistance, natural antibacterial substances are essential in the fight against bacterial illnesses. These substances have a variety of antibacterial qualities and are produced by plants, marine life, and other natural sources as part of their defence mechanisms (Thawabteh et al., 2019; Thawabteh et al., 2021; Thawabteh et al., 2023a). An analysis of antibacterial substances obtained from natural sources is provided in this review.

3.1 Alkaloids

Although they are also found in certain microbes and marine species, alkaloids are a broad and diverse class of nitrogenous chemicals that are mostly derived from plants. They are known to have a variety of biological properties, including potent antibacterial properties. Alkaloids are an important family of chemicals in the hunt for new antibacterial treatments because they often target many pathways linked to bacterial growth and reproduction (Yan et al., 2021; Liu et al., 2020). The antibacterial characteristics of 248 compounds derived from different alkaloids, such as true alkaloids, protoalkaloids, polyamine alkaloids, and pseudoalkaloids, were covered in our article, “Antibacterial Activity and Antifungal Activity of Monomeric Alkaloids,” which was published in MDPI in November 2024 (Thawabteh et al., 2024b).

The study, which was based on 241 papers that were published in peer-reviewed scientific journals in the last 10 years, demonstrated that derivatives of thiazole, isoxazole, quinoline, and imidazole exhibited potent antibacterial activity with minimum inhibitory concentrations (MIC) of less than 1 μg/mL. Regarding their potential use in medicine, these alkaloid derivatives’ strong antibacterial properties are especially intriguing (Thawabteh et al., 2024b). The 32 most potent antibacterial alkaloids examined in our recently released publication (Thawabteh et al., 2024b) are included in Table 1.

TABLE 1. Antibacterial alkaloids.

3.2 Terpenoids

The greatest class of natural products are terpenoids, which are naturally occurring chemicals. They are composed of five-carbon isoprene units that form carbon skeletons. The functional groups created during the condensation of isoprene units using precursors such as deoxyxylulose phosphate and mevalonic acid in the mevalonate-independent route are what distinguish different terpenoids (Porras et al., 2020; Barbosa et al., 2020; Soltani, 2016). β-caryophyllene, limonene, and α-cubebene are common terpenes, whereas β-amyrin and lupeol are triterpenes (Soltani, 2016).

Based on how many isoprene units they contain, terpenoids with antibacterial qualities are categorized. These consist of the following: nor-triterpenoids, triterpenoids (C30, six units), tetraterpenes (C40, eight units), monoterpenoids (C10, two units), sesquiterpenoids (C15, three units), diterpenoids (C20, four units), and saponins. Asteraceae, Lamiaceae, Pinaceae, Apiaceae, Euphorbiaceae, Putranjivaceae, Dioscoreaceae, Meliaceae, Primulaceae, and Scrophulariaceae are among the plant families that contain these chemicals (Porras et al., 2020; Soltani, 2016). Additionally, they are found in bacteria like Streptomyces, marine life including sponges, corals, and algae, and fungi like Aspergillus species (Barbosa et al., 2020).

Antimicrobial and antibiofilm properties are exhibited by monoterpenoids, diterpenoids, and triterpenoids. A natural byproduct of tea tree oil and Cinnamomum longepaniculatum (Lauraceae) leaves, terpinen-4-ol (1 in Figure 2) suppresses quorum sensing and lowers the expression of associated genes (rhlI, rhlR, rhlAB, lasR, lasB, aprA, lasI, plcH, and toxA) (Porras et al., 2020; Zullkiflee et al., 2022; Guzzo et al., 2020). Furthermore, it has MIC values of 1.5, 3.1, and 1.5 μg/mL for S. enteritidis, E. coli, and S. aureus, respectively. Additionally, terpinen-4-ol and ciprofloxacin exhibit synergistic actions against P. aeruginosa (Guzzo et al., 2020).

Thymol and carvacrol (2 and 3 in Figure 2) are isomeric monoterpene compounds derived from thyme plants, including Thymus zygis and Thymus vulgaris (Lamiaceae family). Carvacrol (2-methyl-5-(propan-2-yl)phenol is another phenolic molecule made in thyme, while thymol (2-isopropyl-5-methylphenol) is a phenolic monoterpene and a significant part of thyme essential oil. Both substances are produced by aromatizing γ-terpinene to p-cymene and then hydroxylating it (Kowalczyk et al., 2020; Rathod et al., 2021). In terms of structure, carvacrol has the methyl group in the meta position, while thymol has the methyl group in the para position with respect to the hydroxyl group on the aromatic ring (Kowalczyk et al., 2020; Rathod et al., 2021).

Strong antimicrobial properties are demonstrated by both compounds against both Gram-positive and Gram-negative bacteria, including Salmonella (MIC values of 32 μg/mL for thyme and 50 μg/mL for carvacrol), P. mirabilis (MIC value of 10 μg/mL for thyme), E. coli (MIC values of 45 μg/mL for thyme and 50 μg/mL for carvacrol), S. aureus (MIC values of 25 μg/mL for thyme and the same for carvacrol), and P. aeruginosa (MIC values of 50 μg/mL for carvacrol). By depolarizing cytoplasmic membranes and increasing cell membrane permeability, their antibacterial activity kills bacteria (Chassagne et al., 2021; Song et al., 2021).

Carvacrol exhibits a synergistic impact with nisin, whereas thymol selectively inhibits MRSA biofilm formation by targeting extracellular DNA, polysaccharide intracellular adhesion, and quorum-sensing pathways (Kowalczyk et al., 2020; Rathod et al., 2021). Because of its ability to combat microorganisms present in burns and biofilms, thymol is also recommended for wound healing, especially in third-degree burns, and for preventing UTIs (Chabán et al., 2019).

Carnosic acid (4 in Figure 2), a diterpenoid compound, is extracted from Salvia officinalis and Lepechinia meyenii (both from the Lamiaceae family) using aerial parts of the plants. With MIC values of 7.8–12 μg/mL and 15.6 μg/mL, respectively, it is effective against Gram-positive bacteria, such as S. aureus and E. faecalis (Chabán et al., 2019; Theodoridis et al., 2023). Studies of the structure-activity relationship demonstrate that carnosic acid and its methyl ester derivatives’ carbon 20 lowers the minimum inhibitory concentration (MIC) against E. faecalis and MRSA. Furthermore, antibacterial action depends on carbon 12 (Porras et al., 2020).

Ursolic acid (5 in Figure 2) classified as triterpene saponins compound, is extracted from various plants, including apple (Malus domestica, Rosaceae), Rostellularia procumbens (Acanthaceae), coffee (Coffea arabica, Rubiaceae), cranberry (Vaccinium macrocarpon, Ericaceae), guava (Psidium guajava, Myrtaceae), and marjoram (Origanum species). Both Gram-positive and Gram-negative bacteria are susceptible to its antimicrobial action. It is effective against Gram-positive E. faecalis, L. monocytogenes, and S. aureus, with respective MICs of 1, 2, 100, and µg/mL. With MIC values of 25, 25, 25, 100, and 200 μg/mL, respectively, it is effective against Gram-negative S. typhi, E. coli, P. aeruginosa, V. cholerae, and K. pneumonia (Porras et al., 2020; Dan et al., 2022; Jyoti et al., 2016; Barman et al., 2023; Bouyahya et al., 2022).

Changes at carbons 3, 17, and 28 can improve the solubility and antibacterial activity of ursolic acid. The addition of carbazole or N-(dimethylamino) propyl amide side chains further improves efficacy, whereas acetylation at carbon 3 (ursolic acetate) boosts action. The effectiveness against B. subtilis and S. aureus is enhanced by modifications at carbon 17, such as the addition of a methyl ester group with hydroxyl groups at carbons 1 and 2 (methyl 1α,2β,3β-trihydroxy-urs-12-en-28-oate). By focusing on efflux pumps, the insertion of an n-butyl or isopropyl chain at carbon 28 prevents E. coli resistance (Jyoti et al., 2016; Barman et al., 2023; Bouyahya et al., 2022).

Activity against S. aureus that is resistant to many drugs is increased when aminoguanidine is combined with changes at carbons 3 and 28 (Porras et al., 2020; Chassagne et al., 2021). A partial synergistic action between ursolic acid and oxacillin is demonstrated by its derivative, ursolic acid 3-O-α-L-arabinopyranoside (6 in Figure 2) triterpene saponins, which lowers the MIC to 6.25 μg/mL against S. aureus (Zhou et al., 2017). Ursolic acid and oxacillin together exhibit a MIC of 31.25 μg/mL. Table 2 lists further terpenoids (Zhou et al., 2017).

TABLE 2. Terpenoids with antibacterial activity.

3.3 Phenolics

A broad and varied class of secondary metabolites known as phenolic compounds has at least one phenol group, which is made up of an aromatic ring and a hydroxyl group. These substances are present in almost every plant and have a variety of structures and bioactivities, such as antibacterial, anticancer, anti-inflammatory, and antioxidant qualities. Flavonoids, quinones, coumarins, chalcones, xanthones, tannins, and other similar substances are all considered phenolic compounds (Porras et al., 2020; Alara et al., 2021). Fabaceae, Clusiaceae, Moraceae, Lardizabalaceae, Hypericaceae, Orchidaceae, Rubiaceae, Arecaceae, Asteraceae, and Ebenaceae are among the plant families in which they are found. The Fabaceae family is especially abundant in phenolic compounds among these. The shikimate or acetate routes are used in the biosynthesis of quinones, a subclass of phenolic compounds made up of aromatic rings with two ketone replacements (Porras et al., 2020; Alara et al., 2021).

Natural xanthones can be found in a number of plant groups, such as the Garcinia species of the Clusiaceae family, the Moraceae, the Clusiaceae, the Polygalaceae, and the Gentianaceae. The shikimate-acetate pathway is used in the biosynthesis of compounds that have been identified from these plants and show strong antibacterial action (Kong et al., 2022; Oriola and Kar, 2024). Significant antibacterial action was shown by cheffouxanthone (7 in Figure 2), which was isolated from the stem bark of Garcinia smeathmanii. With MICs of 8, 32, and 64 μg/mL, respectively, it is effective against Gram-positive bacteria such E. faecalis, B. cereus, and S. aureus. With a MIC of 32 μg/mL, it is also effective against the Gram-negative bacterium E. coli (Fouotsa et al., 2015; Salleh et al., 2019).

Derived from the roots of Plumbago indica Linn. and the non-polar bark extract of Diospyros anisandra S.F. Blake, plumbagin (8 in Figure 2) is a potent quinone phenolic compound. This metabolite exhibits broad-spectrum activity, notably against Mycobacterium tuberculosis (both XDR and MDR strains) with MIC values as low as 1.56 and 0.25 μg/mL, respectively. Furthermore, its efficacy extends to Gram-negative pathogens, including S. sonnei, E. coli, and K. pneumoniae, where it maintains MICs of 2, 2, and 32 μg/mL. The compound also demonstrates significant inhibitory effects on Gram-positive species such as S. pneumoniae, S. aureus, S. pyogenes, and B. subtilis, showing MIC values ranging from less than 4–16 μg/mL (Guzzo et al., 2020; Elmaidomy et al., 2022; Periasamy et al., 2019).

Chalcones, characterized as α,β-unsaturated ketones, serve as fundamental precursors in flavonoid biosynthesis. These molecules possess a unique three-carbon α,β-unsaturated carbonyl system linking two aromatic rings-a conjugated structure that facilitates their diverse biological functions (Elkanzi et al., 2022). A prominent example is the prenylated chalcone xanthoangelol (9 in Figure 2), isolated from the roots of Ashitaba (Angelica keiskei). Its biological potency is attributed to the synergistic effect of the α,β-unsaturated carbonyl system, the benzophenone-like backbone, and the presence of prenyl and hydroxyl functional groups (Elkanzi et al., 2022). Experimental data highlights the strong antibacterial potential of xanthoangelol, particularly against Gram-positive bacteria; it yields MIC values of 1.2, 8, 1.2, and 2.5 μg/mL against S. aureus, B. subtilis, E. faecium, and E. faecalis, respectively (Yang et al., 2024; Meier et al., 2019).

Numerous plants contain coumarins, a family of benzopyrone compounds. Because of their vast range of biological functions, these substances are being researched extensively (Mandlik et al., 2016). Both Gram-positive and Gram-negative bacteria are effectively inhibited by coumarins (Qin et al., 2020). With MIC values ranging from 14 to 17 μg/mL, Aegelinol (10 in Figure 2), which has been isolated from plants including Ferulago campestris and Ferulago asparagifolia, has shown significant antibacterial activity against S. typhi, S. aureus, E. cloacae, and E. aerogene (Kubrak et al., 2017; Dikpınar and Süzgeç-Selçuk, 2019). The antibacterial properties of other xanthones, quinones, chalcones, and coumarin derivatives are included in Table 3.

TABLE 3. Lists of other xanthones, quinones, chalcones and coumarins derivatives and their antibacterial activities.

3.4 Glycosides

Derivatives of natural glycosides are bioactive substances that are abundant in plants, marine life, and microorganisms. They have strong antibacterial properties against a variety of bacterial types. The solubility and bioavailability of these compounds are improved by the presence of sugar moieties connected to aglycone components via glycosidic linkages (Zou and Fang, 2021). Numerous glycosides, including steroidal glycosides, flavonoid glycosides, and anthraquinone glycosides, have been identified from Prunus persica, Daphne species, and other sources. These glycosides have been shown to be effective against P. aeruginosa, E. coli, and S. aureus. Inhibition of bacterial cell wall formation, loss of membrane integrity, and interference with vital bacterial enzymes are some of their antibacterial methods. In terms of chemistry, these glycosides are precursors to active substances such as 1,2,3-triazole glycoside clickamers, narbomycin derivatives, and hesperidin glycosides, which are structurally modified to improve their pharmacological characteristics (Elshahawi et al., 2015; De Jesus B Muribeca et al., 2022).

The antibacterial properties of the compounds that were obtained from G. glandulosum, including isorhamnetin-3-O-α-L-rhamnopyranosyl-β-D-glucopyranoside, chrysoeriol-7-O-β-D-apiofuranosyl-β-D-xylopyranoside, and luteolin-7-O-β-D-apiofuranosyl-β-D-xylopyranoside (11–13, Figure 3). Compound 11 had a MIC value of about 128 μg/mL against V. cholerae CO6, whereas compounds 12 and 13 had MIC values of 64 μg/mL against V. cholerae CO6 and 128 μg/mL against C. albicans (Tagousop et al., 2018).

Citrus fruits contain hesperidin (14 in Figure 3), which is made up of hesperetin (the aglycone portion) connected by a glycosidic bond to a disaccharide (rutinose: glucose + rhamnose). Hesperidin’s antibacterial properties have been investigated; it has been shown to exhibit antibacterial activity against a variety of organisms, such as S. aureus and E. coli, frequently with MIC values between 100 and 250 μg/mL (Iranshahi et al., 2015; Choi a al., 2022).

Research shows that the aglycone form of hesperetin (15 in Figure 3) has more antibacterial action than its glycosylated equivalent, hesperidin. Hesperetin’s higher lipophilicity, which promotes improved contact with bacterial membranes, is probably the cause of this enhanced potency. Hesperetin has inhibitory effects on E. coli and P. aeruginosa, with MIC values of 500 μg/mL for both bacteria, and considerable action against S. aureus and Bacillota cereus, with MIC values of 125 μg/mL and 250 μg/mL, respectively (Mariano et al., 2024).

The antibacterial qualities of rutin (16 in Figure 3), a flavonoid glycoside that is widely present in citrus fruits and buckwheat, have been investigated. With MIC values of 128, 512, 256, and 256 μg/mL, respectively, rutin demonstrated antibacterial activity against S. epidermidis ATCC 35984, S. aureus ATCC 25923, E. faecalis ATCC 29212, and Bacillota subtilis PCM 2021. Additionally, with MIC values of 512, 256, 256, 1,024, and 1,024 μg/mL, respectively, it demonstrated action against E. coli ATCC 25922, K. pneumoniae ATCC 27736, P. mirabilis ATCC 7002, P. aeruginosa ATCC 27853, and A. baumannii ATCC 19606 (Negahdari et al., 2020). Additional glycoside substances mentioned in Table 4.

TABLE 4. Glycosides with antibacterial activity.

3.5 Saponins

Natural glycoside substances called saponins are present in a variety of plants. They function as surfactants that dissolve in water and produce foam because of their structure, which consists of a lipophilic genin portion and a hydrophilic sugar group. The biological activity of saponins, which are divided into triterpenoid and steroidal kinds, include hepatoprotective, anticancer, anti-inflammatory, antifungal, antiviral, and antibacterial qualities (Dong et al., 2020).

Alstonia scholaris (Apocynaceae) leaves yielded oleanolic acid (17 in Figure 3), which is also a member of the Oleaceae family. With MIC values of 8, 4, 16, and 50 μg/mL, respectively, it demonstrates antibacterial action against Gram-positive and Gram-negative bacteria, such as L. monocytogenes, E. faecalis, B. cereus, and Mycobacterium TB (Wang C.-M. et al., 2016, Huang et al., 2022). Studies of the structure-activity relationship show that oleanolic acid’s antibacterial activity is increased by adding amide derivatives at carbon 28 and lengthening the chain. Oleanolic acid’s antibacterial activity is further enhanced by the synergistic effects it produces when used with traditional antibiotics. These results demonstrate oleanolic acid’s potential as a promising antibacterial treatment agent (Huang et al., 2022).

Melanthera elliptica (Asteraceae family) produces 3-O-β-D-glucuronopyranosyl-oleanolic acid (18 in Figure 3), which has antibacterial properties. With a MIC value of 8 μg/mL against Gram-positive bacteria like S. aureus and a MIC of 32 μg/mL against Gram-negative bacteria like E. coli, it is especially efficient against these pathogens. In comparison to vancomycin alone (MIC: 2 μg/mL and 32 μg/mL, respectively), this saponin has a synergistic effect when coupled with vancomycin, lowering the MIC for S. aureus to 1 μg/mL and for E. coli to 8 μg/mL. Tetracycline’s antibacterial properties are also strengthened when this saponin is combined with it. These results demonstrate how saponins may increase the potency of already available antibiotics and fight bacterial illnesses that are resistant to them (Dong et al., 2020, Li and Monje-Galvan, 2023).

A saponin molecule that was isolated from Pseudolarix amabilis, pseudololide Q (19 in Figure 3), exhibits significant antibacterial action. For example, it outperforms amoxicillin (MIC 16.84 μg/mL) against Gram-positive bacteria S. aureus (MIC 3.1–6.08 μg/mL) and E. coli (MIC 50 μg/mL). Pseudolarix amabilis saponins and triterpenes exhibit methicillin-resistant S. aureus (MRSA) action with a minimum inhibitory concentration (MIC) of 31.25 μg/mL when coupled with oxacillin (Guo et al., 2017; Zhou et al., 2017). Additional saponin compounds are included in Table 5.

TABLE 5. Saponins with antibacterial activity.

3.6 Polyketides

Polyketides are a class of natural compounds that come from plants, microbes (like Aspergillus), and marine species. These substances are produced by polyketide synthase (PKS) enzymes, which function similarly to how fatty acids are made from malonyl-CoA (MCoA) and acetyl-CoA (CoA) substrates. The varied biological actions of polyketides are attributed to their vast spectrum of complex structures, which include macrolides, polyethers, enediynes, polyphenols, and polyenes (Rodrigues, 2016, Rodrigues, 2022).

Numerous biological characteristics of these substances, such as immunological suppression, cholesterol-lowering effects, antiparasitic activity, and antibacterial efficacy, have been thoroughly investigated. It has been demonstrated that polyketides are efficient against a variety of bacteria, including Gram-positive bacteria like methicillin-resistant MRSA, or S. aureus Commonly used to treat bacterial infections, polyketide antibiotics include erythromycin, clarithromycin, and doxycycline (Rodrigues, 2016, Silva et al., 2020).

Important natural compounds derived from polyketides have also been obtained from marine sources, such as Verrucosispora species. With a minimum inhibitory concentration (MIC) of approximately 4 μg/mL, abyssomicin C (20 in Figure 3) is a polycyclic polyketide that has shown antimicrobial activity against Gram-positive bacteria, including Vancomycin-resistant S. aureus, which has a MIC of 4–13 μg/mL (Thawabteh et al., 2023b). These antibacterial drugs work by preventing the formation of folic acid and interfering with the biosynthesis of para-aminobenzoic acid. Additionally, abyssomicin C exhibits activity against microorganisms that are resistant to antibiotics, including S. aureus that is resistant to vancomycin (Manivasagan et al., 2023).

A polyketide chemical called pestalone (21 in Figure 4) was isolated from both the Rosenvingea and Pestalotia species of marine fungi. With minimum inhibitory concentrations (MIC) of 0.037 and 0.078 μg/mL, respectively, it has demonstrated efficacy against vancomycin-resistant bacteria and methicillin-resistant S. aureus (MRSA) (Thawabteh et al., 2023a, Sridhar et al., 2021). Furthermore, scientists have shown that natural pestalone is more effective than its synthetic counterpart, with the synthetic compound’s MIC for MRSA rising to 6.25 μg/mL (Thawabteh et al., 2023a). Additional polyketide compounds having antibacterial properties are displayed in Table 6.

TABLE 6. Polyketide with antibacterial activity.

3.7 Lignans

Due to the presence of stereoselective enzymes that pair derived coniferyl alcohol moieties, lignans-secondary metabolites made up of ferulic or cinnamic acid residues-are present in natural products (Wang Q. et al., 2022). These substances are byproducts of the manufacture of cinnamic acid in plants, which is linked biochemically to the metabolism of phenylalanine and takes place via the shikimic acid pathway. P-coumaryl alcohol, coniferyl alcohol, and their dimers are significant intermediates that contribute to the formation of lignan molecules (Xu et al., 2021).

Two phenylpropane units joined by β,β′-bonds form the dimeric structure of lignans, which also have different side chain substitutions on the aromatic rings. They originate from the oxidation of sites C3 through C6. Aryltetralin, arylnaphthalene, dibenzylbutane, dibenzylbutyrolactone, dibenzocyclooctadiene, dibenzylbutyrolactol, furofuran, and furan are the eight classes into which lignans are divided. These substances belong to several plant families, including Pedaliaceae, Brassicaceae, Poaceae, Linaceae, Schisandraceae, and Araucariaceae, and are present in a variety of plants, including sesame, flaxseed, linum, and Brassica vegetables. Numerous biological actions, such as anticancer, anti-inflammatory, antioxidant, antiviral, and antibacterial properties, have been linked to lignans (Xu et al., 2021; Sangiorgio et al., 2023).

3′-Demethoxy-6-O-demethylisoguaiacin (22 in Figure 4) is a naturally occurring lignan chemical that is obtained from the leaves of plants like Larrea tridentata. With a MIC range of 12.5–25 μg/mL, it has demonstrated action against S. aureus in antimicrobial investigations (Higuera-Piedrahita et al., 2023). By disrupting ATP-binding cassette (ABC) bacterial transporters, 3′-demethoxy-6-O-demethylisoguaiacin shows synergistic benefits when used in conjunction with traditional antibiotics (Porras et al., 2020).

Ficus foveolate (of the Moraceae family) is the source of foveolatamide (23 in Figure 4), commonly referred to as lignanamides, a tetrahydronaphthalene lignan derivative. With a MIC of roughly 45 μg/mL, foveolatamide demonstrates antibacterial efficacy against S. pyogenes (Meerungrueang and Panichayupakaranant, 2016).

A naturally occurring lignan component, hinokinin (24 in Figure 4) was initially isolated from hinoki tree wood. Additionally, it has been discovered in the stem bark of Commiphora leptophloeos (Burseraceae) and Corymbulosum Reichenb, a member of the Myrtaceae family. With MICs of 134.7 μg/mL, 88.6 μg/mL, 88.6 μg/mL, 88.6 μg/mL, 113.4 μg/mL, and 99.2 μg/mL, respectively, the compound demonstrates antibacterial activity against Gram-positive bacteria, including E. faecalis, S. salivarius, S. sanguinis, S. mitis, S. mutans, and S. sobrinus. Hinokinin is also effective against M. tuberculosis, M. kansasii, and M. avium, with MICs of 62.5 μg/mL, 200 μg/mL, and 500 μg/mL, respectively, and against S. aureus (MRSA) with a MIC of 48.5 μg/mL (De Souza Pereira et al., 2017; Gabr et al., 2016).

Medioresinol (25 in Figure 4) was isolated from the stem bark of Sambucus williamsii and the seeds of Punica granatum L. By preventing the formation of cell walls, more especially the creation of peptidoglycan cross-linking, it demonstrates antibacterial activity. Medioresinol inhibits the function of penicillin-binding proteins by binding to them. With MICs of 2.5, 2.5, and 5 μg/mL, respectively, this chemical exhibits activity against Gram-positive bacteria, including P. acnes, S. aureus, and E. faecium. With MICs of 0.5, 2.5, and 20 μg/mL, respectively, it also has activity against Gram-negative bacteria, such as E. coli O-157, E. coli, and P. aeruginosa (Maphetu et al., 2022; Yassin et al., 2021).

Medioresinol works in concert with antibiotics including ampicillin, cefotaxime, and chloramphenicol to combat P. aeruginosa and P. acnes. Additionally, when combined with (+)-medioresinol, ampicillin or cefotaxime exhibit synergistic benefits against S. aureus. Medioresinol increases antibacterial action against E. coli when coupled with cefotaxime or chloramphenicol. Where 0.6–5 μg/mL is the range of the MIC (Maphetu et al., 2022; Yassin et al., 2021). Additional lignan compounds having antibacterial properties are included in Table 7.

TABLE 7. Lignans with antibacterial activity.

3.8 Amino acids

Organic substances called amino acids are essential for the creation of proteins and other metabolic functions. They are widely distributed in plants, either in free form or as a component of proteins. Research on plant-based amino acids is crucial in the fight against bacteria that are resistant to antibiotics because a number of these amino acids have shown antibacterial qualities (Zhu et al., 2019; Brunetti et al., 2020).

L-lysine is a promising treatment option for bacterial infections, especially those brought on by Gram-positive and Gram-negative pathogens, because it has bacteriostatic and bactericidal properties at moderate MIC values. With MIC values ranging from 100 to 250 μg/mL against S. aureus, 150–300 μg/mL against E. coli, and 120–300 μg/mL against K. pneumoniae, L-lysine has been demonstrated to have antibacterial properties (Švedienė et al., 2021; De Sousa et al., 2024).

The antibacterial qualities of tryptophan, an essential aromatic amino acid, have been investigated and have demonstrated encouraging results against a range of Gram-positive and Gram-negative bacteria. Its capacity to damage bacterial cell membranes, affect tryptophan metabolism, and encourage the immune system’s synthesis of antimicrobial peptides is what gives it its antibacterial properties. With MIC values ranging from 50 to 250 μg/mL, tryptophan has antibacterial activity against S. typhimurium, L. monocytogenes, E. coli, P. aeruginosa, and S. aureus (Elafify et al., 2020; Elafify et al., 2019).

A non-essential amino acid, L-glutamine is required for many biological processes, such as cellular metabolism, immune system support, and protein synthesis. L-glutamine was found to have antibacterial action against S. typhimurium, P. aeruginosa, S. aureus, E. coli, and S. pyogenes, with a minimum inhibitory concentration (MIC) ranging from 150 to 300 μg/mL (Zhao et al., 2021; Yong et al., 2021).

By disrupting the bacterial cell wall and affecting protein synthesis, the sulfur-containing amino acid L-cysteine, which has MIC values ranging from 120 to 250 μg/mL, inhibits the growth of S. pneumoniae. It has also demonstrated effective antimicrobial activity against P. aeruginosa, most likely due to membrane disruption and interference with sulfur-containing metabolites that are necessary for bacterial growth (Wang et al., 2019). Additionally, L-phenylalanine and L-serine, both essential and non-essential amino acids, showed antibacterial action against P. aeruginosa and S. pneumoniae (Haufroid and Wouters, 2019; Sen et al., 2019).

An important amino acid, L-arginine is involved in the creation of nitric oxide and is vital for the immune system. By influencing bacterial cell function, enhancing the immune response, and modifying cytokine production, it has shown antibacterial effectiveness. With a MIC value ranging from 100 to 200 μg/mL, L-arginine has demonstrated inhibitory effects on S. typhimurium, most likely as a result of its function in enhancing immune response, influencing bacterial enzyme activity, and regulating the synthesis of antimicrobial peptides (Sepahi et al., 2017). Furthermore, L-asparagine has been demonstrated to suppress S. typhimurium growth by disrupting bacterial metabolism and perhaps influencing protein synthesis; its minimum inhibitory concentration (MIC) was between 150 and 250 μg/mL (Torres et al., 2015).

Several bacterial strains are susceptible to the antimicrobial effects of L-leucine, L-tyrosine, L-methionine, and glycine. With MIC values for E. faecalis and K. pneumoniae ranging from 150 to 200 μg/mL, L-leucine has considerable activity against both Gram-positive and Gram-negative bacteria (Perinelli et al., 2019; Mukherjee et al., 2018). With MIC values ranging from 100 to 200 μg/mL, L-tyrosine exhibits antibacterial activity against E. coli and B. subtilis due to its aromatic structure (Ravichandran et al., 2017). With MIC values ranging from 150 to 300 μg/mL, L-methionine shows activity against S. pneumoniae and E. coli. This is probably because it contains sulfur, which breaks down bacterial membranes (Perinelli et al., 2019; Zhou et al., 2018). With MIC values ranging from 200 to 350 μg/mL, glycine has demonstrated inhibition against S. aureus and K. pneumoniae (Sathoff and Samac, 2018; Giordano and Barnini, 2024).

3.9 Steroids

Because of their sterol-derived backbone, many steroidal substances generated from plants have antibacterial properties. They can interfere with bacterial metabolism, alter bacterial membranes, or hinder DNA replication. These substances fall into various types, including cardenolides, phytosterols, steroidal saponins, and withanolides (steroidal lactones) (Patel and Savjani, 2015).

Withania somnifera, also known as ashwagandha, is the source of the steroidal lactone Withaferin A (26 in Figure 4), which has strong antibacterial properties against P. aeruginosa and S. aureus. With a MIC of 37.65 μg/mL, it efficiently inhibits S. aureus by rupturing bacterial cell membranes and stopping the formation of biofilms (Murugan et al., 2023). With a MIC of 28.24 μg/mL and an MBC of 37.65 μg/mL, withaferin A exhibits potent antibacterial activity against P. aeruginosa, mainly by bacterial lysis and membrane damage (Murugan et al., 2022). Interestingly, it has been discovered that withaferin A and the broad-spectrum fluoroquinolone antibiotic ciprofloxacin work in concert.

By drastically lowering the necessary MIC and circumventing bacterial resistance mechanisms, this combination increases the antibacterial activity of ciprofloxacin. The synergy is attributed to withaferin A’s ability to disrupt bacterial membrane integrity, thereby facilitating increased intracellular penetration of ciprofloxacin. According to these results, a possible tactic to treat bacterial infections resistant to antibiotics may be to combine Withaferin A with traditional antibiotics such as ciprofloxacin (Murugan et al., 2022; 2023).

The chemical structure of two additional steroidal lactones produced from W. somnifera, withanolide A and withanolide D (27 and 28 in Figure 4), affects their antibacterial activity. For maximum action and selectivity against Gram-positive bacteria, structural characteristics including the presence of an epoxy group at carbons C-5 and C-6 and a tertiary hydroxyl group at C-17—which differs from that of aserin A at C-27—are thought to be crucial (Saleem et al., 2020). Significant antibacterial activity has been demonstrated by withanolide A against S. aureus and Pseudomonas species. Withanolide A may be a useful antibacterial agent, as evidenced by in vitro tests showing that it suppressed the growth of these pathogens at doses of 100, 500, and 1,000 ppm (Lobatto et al., 2023). Withanolide D has also demonstrated encouraging antibacterial action. With MICs ranging from 40 to 1.2 μg/mL, studies show that withanolides, such as Withanolide D, have antibacterial qualities against S. aureus (Srivastava et al., 2018).

When used with currently available antibiotics, withanolides A and D have demonstrated synergistic effects. The synergistic benefits of W. somnifera methanolic extracts, which are high in withanolides A and D, with antibiotics such trimethoprim, ceftazidime, and chloramphenicol against isolates of S. Typhi that are resistant to several drugs have been investigated. Withanolides may increase the effectiveness of these antibiotics, as seen by the combination therapy’s increased antibacterial activity (Dwivedi et al., 2019).

β-Sitosterol (29 in Figure 4), a plant-derived sterol (phytosterols), has proven antibacterial activity against diverse bacterial strains. β-sitosterol had a MIC of 1.24 mg/mL and an MBC of 2.208 mg/mL against S. aureus in a study conducted on Odontonema strictum leaves (Luhata and Usuki, 2021). According to a different study, at a concentration of 10 µg/well, β-sitosterol extracted from Parthenium hysterophorus leaves had strong antibacterial activity against V. anguillarum and V. harveyi, with zones of inhibition measuring 19 mm and 17 mm, respectively (Ravi et al., 2020). Additionally, β-sitosterol-D-glucopyranoside (30 in Figure 4), produced from Desmostachya bipinnata leaves, displayed modest antibacterial activity against E. coli, with a MIC of 25,000 ppm and an MBC of 50,000 ppm (Gupta, 2020).

In terms of synergistic effects, ciprofloxacin and β-sitosterol-D-glucopyranoside showed increased antibacterial activity. MIC values were significantly reduced as a result of this combination, demonstrating the potential of β-sitosterol derivatives as supplements to current antibiotic treatments (Gupta, 2020). Additionally, according to molecular docking studies, β-sitosterol may have antibacterial properties by inhibiting bacterial dihydrofolate reductase (DHFR), an enzyme essential for the production of folic acid (Luhata and Usuki, 2021). Table 8 contains more steroid compounds with antibacterial properties.

TABLE 8. Antibacterial steroids.

4 Challenges in the use of plant-derived natural products

Natural medicines made from plants have a lot of potential as antibacterial agents, particularly as worries about antibiotic resistance continue to rise. For its safe and successful integration into clinical practice, a number of issues need to be resolved.

The possible toxicity and negative health effects of plant-derived antibacterial agents are one of the main obstacles to their use. Although numerous plants have demonstrated antibacterial qualities in lab tests, it is frequently unclear how safe these substances are for people. Certain substances originating from plants may trigger allergic reactions in sensitive people or have harmful effects on important organs. For instance, although alkaloids, terpenoids, and flavonoids are efficient antimicrobials, improper dosage can occasionally cause hepatotoxicity or nephrotoxicity as side effects (Gupta et al., 2017; Choi W.-S. et al., 2017). Therefore, it is essential to guarantee the safety of plant-based medicines before using them on humans.

Variability in the concentration of active chemicals in goods obtained from plants is another major obstacle. Plant species, geographic location, ambient variables, and even the extraction technique can all affect how effective these chemicals are (Kumari and Kotecha, 2016). Without sufficient standardization and quality control methods, the strength of a plant-derived antibiotic might vary substantially from batch to batch, leading to uneven treatment effects (Dhami and Mishra, 2015). To guarantee that the finished product retains a constant and efficient quantity of active substances, regulated extraction techniques and quality control are essential.

Plant-derived chemicals are susceptible to the emergence of bacterial resistance, just like manufactured antibiotics. Studies have demonstrated that bacteria can eventually become resistant to plant-based antimicrobials, despite the common belief that these substances are less likely to cause resistance (Wang Y. et al., 2022). In bacteria exposed to antibiotics generated from plants, resistance mechanisms include efflux pumps, enzymatic degradation, and target site alteration have been noted. It is crucial to use these substances in conjunction with other treatments, alternate plant-derived drugs frequently, and carry out more study to comprehend the mechanisms by which resistance to these natural products arises in order to reduce the likelihood of resistance (Mohanty P. et al., 2021).

Furthermore, it takes a long and intricate process to find an antibacterial agent derived from plants and put it into clinical use. There are several plant-based substances that may have antibacterial qualities, but obtaining regulatory approval and finding therapeutic use are difficult tasks. A plant-derived antibiotic must pass stringent testing, such as preclinical research, clinical trials, and safety and effectiveness evaluation, before it can be used in clinical settings (Wu et al., 2020). These procedures can be time-consuming and expensive. Furthermore, natural goods’ regulatory frameworks are frequently less clear, which might cause delays in their approval. To guarantee the safety and efficacy of these products in human populations, clinical trials must also follow stringent guidelines (Anand et al., 2019).

A mechanistic interpretation of the reviewed compounds indicates that phytochemicals may counter bacterial resistance through several molecularly distinct but often overlapping pathways. Phenolic quinones and related redox-active compounds can interfere with bacterial viability by promoting oxidative stress, disturbing redox homeostasis, and modifying proteins involved in essential metabolic or enzymatic processes, which may partly explain the strong activity reported for plumbagin, thymoquinone, emodin, and related quinone derivatives against Gram-positive bacteria, Gram-negative bacteria, and MDR/XDR Mycobacterium tuberculosis (Guzzo et al., 2020; Periasamy et al., 2019; Elmaidomy et al., 2022; Mohanty et al., 2021a; Dahlem et al., 2022). Xanthones and chalcones may act through additional mechanisms related to membrane interaction, inhibition of bacterial enzymes, and interference with resistance-associated pathways; the presence of prenyl, hydroxyl, and α,β-unsaturated carbonyl functionalities may enhance lipophilicity, membrane affinity, and reactivity with bacterial molecular targets (Fouotsa et al., 2015; Salleh et al., 2019; Elkanzi et al., 2022; Elkanzi et al., 2022; Yang et al., 2024). Terpenoids and triterpenoids, particularly thymol, carvacrol, terpinen-4-ol, ursolic acid, and oleanolic acid derivatives, are frequently associated with perturbation of membrane integrity, dissipation of the proton motive force, increased permeability, inhibition of quorum-sensing-regulated virulence, and antibiofilm effects, thereby weakening bacterial survival and enhancing susceptibility to conventional antibiotics (Porras et al., 2020; Guzzo et al., 2020; Kowalczyk et al., 2020; Rathod et al., 2021; Chassagne et al., 2021; Zhou et al., 2017; Huang et al., 2022). Alkaloids may contribute through diverse mechanisms, including interaction with nucleic acids, disruption of cell division or protein synthesis, inhibition of bacterial enzymes, and modulation of efflux-related resistance, although the exact mechanism varies substantially according to scaffold type and substitution pattern (Yan et al., 2021; Liu et al., 2020; Thawabteh et al., 2024b). Glycosides and saponins may show variable direct antibacterial activity, but their sugar moieties and amphiphilic structures can influence solubility, membrane interaction, and antibiotic potentiation; in particular, saponin-like structures may enhance membrane permeability or facilitate synergistic effects with antibiotics such as vancomycin and tetracycline (Zou and Fang, 2021; Tagousop et al., 2018; Dong et al., 2020; Li and Monje-Galvan, 2023). Therefore, the antibacterial relevance of phytochemicals should be interpreted not only from MIC values, but also from mechanistic evidence linking chemical features to bacterial targets, resistance pathways, and antibiotic-sensitizing effects.

Building on this mechanistic interpretation, the reviewed phytochemical classes can be comparatively evaluated according to antibacterial potency, spectrum of activity, mechanistic relevance, and translational feasibility. Across the reported data, phenolic quinones, xanthones, and chalcones frequently show strong antibacterial activity, including sub-to low-microgram MIC values against clinically relevant Gram-positive pathogens and, in selected cases, MDR/XDR Mycobacterium tuberculosis (Fouotsa et al., 2015; Salleh et al., 2019; Periasamy et al., 2019; Elmaidomy et al., 2022; Yang et al., 2024). These scaffolds are therefore among the most promising candidates for further optimization, particularly when their activity can be linked to defined mechanisms such as membrane disruption, redox imbalance, enzyme inhibition, or interference with resistance-associated pathways (Porras et al., 2020; Guzzo et al., 2020; Chassagne et al., 2021). Selected alkaloids, especially isoquinoline, benzophenanthridine, indole, acridine, and polyamine alkaloids, also emerge as high-priority scaffolds because several representatives combine potent MIC values with broad antibacterial spectra and mechanistic diversity (Yan et al., 2021; Liu et al., 2020; Thawabteh et al., 2024b). Terpenoids and triterpenoids appear especially valuable where antibiofilm effects, membrane perturbation, quorum-sensing inhibition, or antibiotic synergy are reported, although their hydrophobicity and formulation challenges require careful consideration (Porras et al., 2020; Guzzo et al., 2020; Kowalczyk et al., 2020; Rathod et al., 2021; Zhou et al., 2017). By contrast, many glycosides and saponins show more variable direct antibacterial potency, but their structural tunability, amphiphilic properties, and ability to enhance antibiotic activity suggest potential value as adjuvant or lead-optimization platforms (Zou and Fang, 2021; Tagousop et al., 2018; Dong et al., 2020; Li and Monje-Galvan, 2023). Based on this comparative synthesis, future translational prioritization should focus on compounds that satisfy multiple criteria rather than MIC potency alone: reproducible activity against MDR/XDR clinical isolates, mechanistic validation, selectivity over mammalian cells, pharmacokinetic feasibility, chemical accessibility, and synergy with clinically used antibiotics (Horcajada et al., 2019; Catalano et al., 2022).

4.1 Mechanistic insights, cytotoxicity, and clinical evidence

Major phytochemical classes exhibit diverse antibacterial mechanisms targeting bacterial cell integrity, metabolism, and resistance pathways. Phenolic compounds (quinones, xanthones, chalcones) disrupt cytoplasmic membranes, alter proton motive force, inhibit key redox enzymes, and modulate quorum sensing, reducing biofilm formation and virulence (Guzzo et al., 2020; Elkanzi et al., 2022; Yang et al., 2024). Alkaloids (isoquinolines, benzophenanthridines) inhibit enzymes, intercalate DNA, and disrupt replication (Thawabteh et al., 2024b). Terpenoids and triterpenoids, including ursolic acid derivatives and carnosic acid, increase membrane permeability and inhibit efflux pumps, enhancing intracellular accumulation of antibacterial agents (Porras et al., 2020; Barman et al., 2023).

While many phytochemicals show potent in vitro activity, cytotoxicity and clinical evidence remain limited. Some compounds, such as ursolic acid and berberine, have demonstrated relative safety in mammalian cell models at antibacterial concentrations (Barman et al., 2023; Thawabteh et al., 2024b). Saponins and glycosides require careful dosing due to potential hemolytic activity. Few phytochemicals, e.g., berberine and curcumin derivatives, have been evaluated in small-scale clinical trials, but robust evidence against MDR/XDR pathogens in humans is scarce (Elmaidomy et al., 2022; Guzzo et al., 2020).

These mechanistic, cytotoxicity, and clinical features are summarized in Table 9, which provides a comparative overview of major phytochemical classes, their representative compounds, antibacterial mechanisms, cytotoxicity profiles, and available clinical evidence.

TABLE 9. Summary of phytochemical classes, mechanisms, cytotoxicity, and clinical evidence.

4.2 Translational and clinical prioritization of phytochemicals

While MIC values provide initial insight into antibacterial potency, they alone are insufficient to guide clinical or translational development. To prioritize plant-derived compounds for further study, a tiered framework integrating multiple criteria is recommended (Table 10). Criteria include MIC potency against MDR/XDR clinically relevant isolates, mechanistic validation, cytotoxicity and selectivity for mammalian cells, pharmacokinetic feasibility, and reproducible synergy with approved antibiotics. Compounds in Tier 1 represent the most promising candidates for translational research, exhibiting strong in vitro efficacy, low cytotoxicity, and well-characterized mechanisms. Tier 2 compounds may require structural optimization, formulation improvements, or combination strategies to enhance translational potential. Tier 3 compounds have limitations that currently prevent immediate progression to preclinical or clinical studies but may serve as scaffolds for chemical modification or adjuvant therapy (Guzzo et al., 2020; Porras et al., 2020; Barman et al., 2023).

TABLE 10. Translational prioritization (tiered system).

5 Future directions and research needs

Natural compounds originating from plants have a vast amount of potential as antibacterial agents; nevertheless, in order to fully realize their therapeutic potential, future research must investigate novel technologies and methodologies. These plant derivatives must be co-opted for incorporation into contemporary treatments, biotechnological methods must be improved in efficacy, and emerging technologies in natural product discovery must be utilized and maximized (Ahmed et al., 2023).

The identification of novel antibacterial chemicals originating from plants is being transformed by modern technologies like high-throughput screening, bioinformatics, and genomic mining. Through the use of genomic mining, scientists can investigate plant genomes and discover new biosynthetic pathways that generate antimicrobial chemicals, including ones that were previously unknown to science (Pietropaolo et al., 2018). Scientists can forecast these compounds’ chemical structures and evaluate their antibacterial properties by using bioinformatics techniques, which makes screening and discovery procedures more effective (Pietropaolo et al., 2018). Additionally, millions of plant extracts can be rapidly tested against different bacterial strains using high-throughput screening techniques, which speeds up the process of identifying potential candidates (Ayon, 2023). Novel plant-based antibacterial compounds that could otherwise go undetected are being discovered thanks to these approaches (Pietropaolo et al., 2018; Ayon, 2023).

The restricted availability and occasionally low effectiveness of plant-derived antibacterial medicines are two of their main drawbacks. Biotechnological methods, such as synthetic biology and genetic engineering, have the potential to maximize the production of these substances. Plants can be genetically engineered to produce more bioactive chemicals or even new compounds with improved antibacterial qualities (Ruhil et al., 2024). Furthermore, the constraints of conventional agricultural production can be circumvented by using synthetic biology techniques to create microbes or cell cultures that more effectively synthesize chemicals derived from plants (Gupta et al., 2021). Plant-based antimicrobials may become increasingly accessible for therapeutic usage as a result of scalable and sustainable production techniques (Ruhil et al., 2024; Gupta et al., 2021).

Additionally, using chemicals produced from plants as part of a comprehensive strategy to address antibiotic resistance is one possible avenue. This would entail mixing traditional antibiotics with plant-based antimicrobials to produce more potent therapies and slow the emergence of resistance (AlSheikh et al., 2020). Combinatorial treatments that employ substances derived from plants may also be able to address bacterial illnesses from several perspectives, increasing their effectiveness and lowering the risk of resistance. Building on the comparative and mechanistic prioritization outlined above, a critical consideration is that antibacterial potency alone is insufficient to define the translational value of plant-derived metabolites. Many phytochemicals show promising MIC values in vitro, yet fail to progress toward clinical use because of poor aqueous solubility, limited oral bioavailability, rapid metabolic degradation, low systemic exposure, insufficient metabolic stability, and uncertain tissue distribution (Gupta et al., 2017; Choi W.-S. et al., 2017; Horcajada et al., 2019).

In addition, compounds that act through membrane perturbation or redox imbalance may raise selectivity concerns if antibacterial activity is accompanied by mammalian cytotoxicity, hemolysis, mitochondrial toxicity, hepatotoxicity, nephrotoxicity, or non-specific protein reactivity; such toxicity concerns are particularly relevant for certain alkaloids, terpenoids, and flavonoids when dose, exposure, and therapeutic index are not adequately defined (Gupta et al., 2017; Choi W.-S. et al., 2017; Thawabteh et al., 2019; Thawabteh et al., 2021). Other barriers include variability in plant source, extraction method, compound purity, MIC testing conditions, bacterial strain selection, and the frequent absence of standardized pharmacokinetic, toxicological, and in vivo efficacy data (Stan et al., 2021; Porras et al., 2020; Catalano et al., 2022).

From a regulatory perspective, phytochemical development is further complicated by batch-to-batch reproducibility, quality-control requirements, scalable manufacturing, intellectual-property limitations, and the need to define whether a candidate is being developed as a purified active pharmaceutical ingredient, a standardized botanical product, or an antibiotic adjuvant (Horcajada et al., 2019; Catalano et al., 2022). Therefore, future prioritization should not rely exclusively on low MIC values, but should integrate reproducibility across MDR/XDR clinical isolates, molecular mechanism validation, cytotoxicity and selectivity profiling, metabolic stability, pharmacokinetic feasibility, formulation strategy, manufacturability, regulatory pathway clarity, and evidence of synergy with approved antibiotics (Horcajada et al., 2019; Catalano et al., 2022). Such a translational framework would improve the practical value of phytochemical screening and help distinguish promising antibacterial leads from compounds with limited therapeutic applicability. In order to ensure that plant-based antimicrobials can reach their intended targets in the human body, research should also concentrate on creating formulations that enable improved bioavailability (AlSheikh et al., 2020; Cock et al., 2017).

6 Conclusion

The increasing global concern regarding antibiotic resistance underscores the urgent need for alternative antibacterial strategies. Phytochemical interventions represent a promising avenue for combating bacterial infections, particularly in the face of MDR and XDR pathogens. Plant-derived metabolites, such as alkaloids, terpenoids, phenolics, saponins, and glycosides, have demonstrated remarkable antibacterial properties across both Gram-positive and Gram-negative bacteria. These compounds offer diverse mechanisms of action, including disruption of bacterial cell walls and membranes, inhibition of metabolic and enzymatic pathways, interference with bacterial DNA replication, modulation of efflux-related resistance, inhibition of quorum-sensing networks, and disruption of biofilm formation, making them attractive candidates for the development of next-generation antibacterial agents.

Despite their promising potential, several challenges remain. These include variability in the concentration of bioactive compounds due to plant species, geographic origin, cultivation conditions, harvesting stage, extraction methods, and compound-purification procedures, as well as the possible toxicity of certain plant metabolites. Standardization of plant-derived products, along with rigorous safety and efficacy testing, is essential before their integration into clinical practice. Moreover, while these natural compounds have shown potent antibacterial effects in laboratory settings, their clinical application is often hindered by limited aqueous solubility, poor bioavailability, rapid metabolic degradation, uncertain metabolic stability, insufficient pharmacokinetic characterization, limited tissue exposure, and the complexity of developing scalable and reproducible production methods.

A major gap in the current literature is that many phytochemicals are still evaluated primarily on the basis of in vitro MIC values, without sufficient integration of mechanistic validation, cytotoxicity and selectivity profiling, pharmacokinetic feasibility, and in vivo efficacy. Inconsistent MIC reporting, differences in bacterial strain selection, limited testing against clinically relevant MDR/XDR isolates, and insufficient standardization of experimental protocols further complicate cross-study comparison and scaffold prioritization. Therefore, future development should prioritize phytochemical scaffolds that combine reproducible antibacterial potency with defined mechanisms of action, acceptable safety margins, chemical accessibility, metabolic stability, formulation feasibility, and evidence of synergy with approved antibiotics.

Future research must focus on the application of advanced technologies such as high-throughput screening, bioinformatics, and genomic mining to uncover novel plant-based antibacterial agents. Moreover, the use of synthetic biology and genetic engineering could enhance the production of plant metabolites, ensuring their sustainable and scalable availability. Additionally, combination therapies involving plant-derived compounds and conventional antibiotics may offer a strategic approach to overcoming resistance mechanisms and improving therapeutic outcomes. A coherent roadmap for advancing phytochemical-based antibacterial discovery should include standardized antimicrobial testing, comparative scaffold prioritization, structure-activity relationship studies, mechanism-of-action validation, formulation or delivery optimization, in vivo infection models, and early assessment of manufacturability and regulatory feasibility.

Overall, the major contribution of this review is the integration of phytochemical diversity with antibacterial potency, resistance-targeting mechanisms, comparative scaffold prioritization, and translational limitations, thereby providing a critical framework for selecting plant-derived metabolites with realistic potential for further antibacterial development.

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Footnotes

Edited by: Padam Acharya, Eastern Kentucky University - Lancaster Campus, United States

Reviewed by: Neha Khandelwal, Massachusetts General Hospital and Harvard Medical School, United States

Cristián Quintero, Juan Agustín Maza University, Argentina