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1 July 2026

24 Pages

Plant Secondary Metabolites as Next-Generation Antibiofilm and Antimicrobial Agents: Mechanisms, Synergistic Effects, and Clinical Translation

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and
1
School of Pharmacy, Lincoln University College, Petaling Jaya 47301, Malaysia
2
School of Pharmacy, KPJ Healthcare University, Nilai 71800, Malaysia
*
Authors to whom correspondence should be addressed.
Drugs Drug Candidates2026, 5(3), 38;https://doi.org/10.3390/ddc5030038
This article belongs to the Section Drug Candidates from Natural Sources
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Abstract

One of the most pressing challenges facing healthcare today is the rise of biofilm infections and antibiotic-resistant bacteria, which demand entirely new therapeutic strategies beyond conventional antibiotic reliance. A biofilm is a structured community of microorganisms encased in a self-produced extracellular polymeric substance (EPS) matrix, which confers resistance to host immune defenses and antimicrobial agents. Accumulating evidence demonstrates that plant-derived secondary metabolites—including flavonoids, phenolic acids, tannins, terpenoids, and alkaloids—exert potent antibacterial and antibiofilm activities through diverse mechanisms of action. These natural compounds inhibit biofilm formation by disrupting bacterial adhesion, suppressing quorum sensing, degrading the EPS matrix, and impairing bacterial motility. Beyond independent bioactivity, phytochemicals demonstrate significant synergistic potential when combined with conventional antibiotics, revitalizing antimicrobial efficacy against drug-resistant pathogens. Nanoformulation and biogenic carrier technologies further enhance the bioavailability and therapeutic potency of these compounds. Despite these advances, critical challenges persist, including poor bioavailability, physicochemical instability, dose-dependent toxicity, and the risk of resistance development. This review presents a critical and integrative analysis of the pharmacological mechanisms of plant secondary metabolites, with particular emphasis on their role in combating biofilm-associated infections and antibiotic resistance, and discusses translational opportunities including structure–activity relationship (SAR)-guided optimization, high-throughput screening platforms, and advanced drug delivery systems. Collectively, plant secondary metabolites represent a scientifically compelling and clinically relevant pipeline for the development of next-generation antimicrobial and antibiofilm therapeutics.

1. Introduction

A biofilm is a structured community of microbial organisms that adhere to surfaces and are enclosed within a self-generated EPS matrix. Recurrent and chronic infections are frequently associated with biofilm formation, as this community architecture enables microorganisms to persist under hostile environmental conditions [1]. The EPS matrix facilitates waste removal and nutrient retention while simultaneously providing structural protection. Critically, this matrix impairs antibiotic penetration, contributing substantially to the elevated resistance observed in biofilm-associated bacteria [2]. Biofilm-forming bacteria differ markedly from their planktonic counterparts, exhibiting altered phenotypes including reduced metabolic activity and upregulation of resistance-associated genes [3]. Quorum sensing (QS) is essential for biofilm formation and structural maintenance, coordinating gene expression in a cell-density-dependent manner that governs virulence, biofilm development, and antimicrobial resistance [1]. The clinical significance of this association is evident from studies demonstrating that biofilm-forming strains of Klebsiella pneumoniae exhibit greater resistance to multiple antibiotic classes compared to non-biofilm-forming counterparts [4]. Figure 1 illustrates the EPS matrix, bacterial cell architecture, and key mechanisms underlying antibiotic resistance within the biofilm structure.
Figure 1. Biofilm structure and resistance mechanisms. A schematic representation of a mature biofilm illustrating the extracellular polymeric substance (EPS) matrix, embedded bacterial cells, and key resistance mechanisms including restricted antibiotic penetration, efflux pump activation, persister cell formation, and quorum sensing-mediated adaptive resistance. Solid arrows indicate the direction of antibiotic penetration and active efflux; the dotted circular arrow represents the quorum sensing signaling cycle coordinating biofilm maturation; the green shading denotes the EPS matrix, while bacterial cells embedded within the matrix are shown in contrasting color for clarity.
Biofilms present formidable therapeutic challenges due to their multifactorial resistance mechanisms. Effective treatment requires targeted approaches capable of simultaneously addressing EPS matrix dissolution, bacterial adhesion inhibition, and quorum sensing disruption [5,6]. Antimicrobial peptides (AMPs) have attracted considerable research attention for their demonstrated efficacy in inhibiting biofilm formation and combating multidrug-resistant bacterial infections [7]. Nanoparticle-based strategies represent an additional avenue of interest, with metal oxide nanoparticles demonstrating biofilm breakdown and enhanced antibacterial effects by improving antimicrobial agent delivery to target cells [8]. Bacteriophage therapy has also emerged as a promising alternative, with phage-derived depolymerases capable of degrading the EPS matrix and potentiating antimicrobial activity [9].
Plant-derived secondary metabolites and phytochemicals have demonstrated substantial efficacy as antibacterial and antibiofilm agents, representing a scientifically sound alternative or adjunct to standard antibiotics, particularly against drug-resistant pathogens. These compounds inhibit biofilm production by targeting quorum sensing, bacterial motility, cell adhesion, and reactive oxygen species production through mechanisms distinct from those of conventional antibiotics [10].
Polyphenols constitute a particularly well-characterized class of plant-derived compounds with potent antibiofilm activity, disrupting biofilm development by modifying bacterial surface hydrophobicity, degrading the extracellular matrix, altering carbohydrate metabolism, and inhibiting coaggregation [11]. Antibiofilm molecules have also been identified from marine microorganism-derived secondary metabolites; for instance, products of Nocardiopsis lucentensis EMB25 prevent and eradicate Pseudomonas aeruginosa biofilms by targeting QS regulatory proteins LasR and RhlR [12]. Marine bacteria’s secondary metabolites additionally exhibit antibiotic properties against drug-resistant organisms, including MRSA and VRE [13]. Furthermore, secondary metabolites of Sansevieria trifasciata have been shown to possess antibacterial and antibiofilm activity against Pseudomonas aeruginosa, with neophytadiene identified as the principal bioactive constituent in the leaf ethanolic extract [14].

2. Objective

Although a considerable body of literature exists on the antimicrobial properties of plant-derived secondary metabolites, a comprehensive and mechanistically focused review specifically addressing their role in combating bacterial biofilms, quorum sensing, and antibiotic resistance—while simultaneously examining clinical translation challenges and nanotechnology-based delivery innovations—remains lacking. The novelty of the present review lies in its integrative approach: it systematically examines the pharmacological mechanisms of flavonoids, phenolic acids, tannins, terpenoids, and alkaloids against both planktonic bacteria and biofilm-forming pathogens, evaluates synergistic interactions with conventional antibiotics, and critically appraises emerging strategies such as structure–activity relationship (SAR)-guided optimization and biogenic nanocarrier development.
Specifically, this review aims to: (i) provide a comprehensive mechanistic analysis of five major classes of plant secondary metabolites—flavonoids, phenolic acids, tannins, terpenoids, and alkaloids—with respect to their antibacterial and antibiofilm activities; (ii) evaluate their synergistic potential in combination with conventional antibiotics against clinically relevant drug-resistant pathogens; (iii) critically assess the current limitations of these compounds, including poor bioavailability, instability, and resistance development; and (iv) identify specific, evidence-based directions for future translational research. This review is intended to serve as a comprehensive reference for researchers and clinicians engaged in the development of next-generation antibiofilm and antimicrobial therapeutics.

3. Methodology

3.1. Search Strategy

A comprehensive literature search was conducted to identify peer-reviewed studies investigating the antibiofilm and antimicrobial activities of plant secondary metabolites, including flavonoids, phenols, tannins, terpenoids, and alkaloids. The search was performed using PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and ScienceDirect, covering publications from January 2000 to October 2025.
The following keyword combinations and Boolean operators were employed: (“plant secondary metabolites” OR “phytochemicals” OR “flavonoids” OR “phenols” OR “tannins” OR “terpenoids” OR “alkaloids”) AND (“antibiofilm” OR “biofilm inhibition” OR “quorum sensing” OR “EPS disruption”) AND (“antimicrobial” OR “antibacterial” OR “antifungal”) AND (“synergy” OR “synergistic effect” OR “combination therapy”) AND (“clinical translation” OR “bioavailability” OR “drug delivery” OR “nanoparticles”). Additional manual searches were performed using the reference lists of retrieved articles.

3.2. Inclusion and Exclusion Criteria

Inclusion criteria: Original research articles, clinical trials, and systematic reviews published in English reporting in vitro or in vivo antibiofilm and/or antimicrobial activity of at least one class of plant secondary metabolite, describing mechanisms of action, evaluating synergistic effects with conventional antibiotics, or addressing delivery strategies or clinical translation challenges.
Exclusion criteria: Non-English publications, conference abstracts, editorials, and opinion pieces without primary data; studies focusing exclusively on primary metabolites; reports on synthetic or semi-synthetic derivatives without reference to the parent natural compound; and studies lacking quantitative data on biofilm inhibition or antimicrobial activity.

4. Overview of Secondary Metabolites

Secondary metabolites are organic compounds that are non-essential for the basic growth, development, and reproduction of an organism, but that play critical roles in ecological interactions and environmental adaptation. In plants, these compounds function in defense against herbivores and microbial pathogens, in the attraction of pollinators, and in allelopathic competition with neighboring plants. In microorganisms, secondary metabolites serve as antibiotics against competing organisms and facilitate symbiotic relationships [15]. Major ecological roles include defense against pathogens and herbivores [16], allelopathic competition [17], pollinator and seed disperser attraction [18], response to abiotic stress [19], and facilitation of symbiotic interactions [20]. Major classes include alkaloids, flavonoids, terpenoids, phenolic compounds, and polyketides [21].

4.1. Alkaloids

Alkaloids are nitrogen-containing organic compounds exhibiting pronounced biological activity in animals and humans, serving a protective function in plants against herbivory. They are classified into heterocyclic alkaloids (containing a nitrogen heterocyclic ring; e.g., caffeine from Coffea spp., nicotine from Nicotiana spp., and morphine from Papaver somniferum) and non-heterocyclic alkaloids (derived from amino acids; found in Corydalis and Erythroxylum coca) [21].

4.2. Flavonoids

Flavonoids are a major class of polyphenolic compounds widely recognized for their antioxidant activities, protecting plants against disease and UV radiation and contributing to pollination by determining flower pigmentation and fragrance. The flavonoid core consists of two aromatic rings connected by a 15-carbon heterocyclic ring. Major subclasses include flavanols (quercetin, kaempferol, myricetin; berries, onions, apples), flavones (apigenin, luteolin; celery, parsley), isoflavones (daidzein, genistein; soybeans), and anthocyanins (cyanidin, delphinidin; blue and red fruits). Flavonoids possess anti-inflammatory, anti-cancer, and antioxidant properties and occur in Vaccinium spp., Citrus sinensis, and Camellia sinensis [22,23].

4.3. Terpenoids

Terpenoids (isoprenoids) represent the largest and most structurally diverse class of plant secondary metabolites, composed of isoprene (C5) units. Major subclasses include monoterpenes (C10; limonene from citrus fruits, menthol from Mentha spp.), sesquiterpenes (C15; bisabolol from Chamomilla recutita), diterpenes (C20; taxol, gibberellins), triterpenes (C30; squalene, betulinic acid from Betula spp.), and tetraterpenes (C40; carotenoids). Terpenoids are widely distributed in essential oils, resins, and volatile compounds of Cannabis sativa and Artemisia annua [24].

4.4. Phenolic Compounds

Phenolic compounds are aromatic molecules bearing one or more hydroxyl groups bonded to aromatic rings, playing a critical role in plant defense against predators, UV irradiation, and microbial infection. Key categories include phenolic acids (ferulic acid, caffeic acid, p-coumaric acid; cereals, coffee, grapes), flavonoids, and tannins—large polyphenolic compounds with astringent properties including gallotannins from oak and chestnut trees. Phenolic compounds are abundant in tea, wine, fruits, and vegetables and exhibit high antioxidant activity with demonstrated benefits in cancer and cardiovascular disease prevention [25].

4.5. Polyketides

Polyketides are chemically diverse compounds produced by plants, microorganisms, and fungi through enzymatic pathways catalyzed by polyketide synthases. They exhibit antibiotic, antifungal, and anticancer activities. Important subclasses include macrolides (erythromycin), aminoglycosides (streptomycin), and fungal polyketides (lovastatin from Aspergillus terreus) [26].

5. Antibiofilm Activity of Plant Secondary Metabolites

Bacterial biofilms are structured communities of microorganisms that adhere to surfaces and produce a protective polymeric matrix, rendering them highly resistant to antimicrobial agents and host immune defenses. Due to the intrinsic resistance conferred by biofilm architecture, these communities persist on biological tissues and medical devices, representing a major clinical challenge [24].

5.1. Mechanism of Action

Table 1 (below) provides a comprehensive summary of the antibiofilm mechanisms of five major classes of plant secondary metabolites—flavonoids, phenolic acids, terpenoids, tannins, and alkaloids—against clinically relevant bacterial pathogens.
Table 1. Mechanisms of antibiofilm action of plant secondary metabolites against clinically relevant bacterial pathogens, including representative molecular formulae.
The mechanistic landscape of plant secondary metabolite antibiofilm activity can be organized into five principal categories: (i) inhibition of bacterial adhesion; (ii) quorum sensing suppression; (iii) EPS matrix degradation; (iv) bacterial cell membrane disruption; and (v) inhibition of bacterial motility.
Flavonoids exert antibiofilm effects primarily through disruption of biofilm matrix structural integrity and suppression of quorum sensing via inhibition of acyl-homoserine lactone (AHL) signaling. Quercetin simultaneously inhibits EPS synthesis, blocks QS-mediated signaling, and disrupts cell membrane integrity. Kaempferol prevents bacterial adhesion and inhibits QS-regulated gene expression, while apigenin and luteolin suppress EPS matrix synthesis and downregulate virulence factor expression.
Phenolic acids disrupt biofilm formation through complementary mechanisms. Gallic acid degrades the EPS matrix by downregulating matrix biosynthesis genes and disrupting AHL signaling. Caffeic acid prevents bacterial motility by interacting with flagellar proteins and modifies bacterial surface hydrophobicity. Ferulic acid inhibits QS communication and modifies microbial surface charge to prevent surface adherence.
Among terpenoids, betulinic acid—a pentacyclic triterpenoid from Betula spp.—disrupts biofilm formation by inserting into the bacterial lipid bilayer, blocking autoinducer synthesis, and degrading EPS. Its demonstrated synergistic activity with β-lactam antibiotics against MRSA lends it significant translational relevance. Asiaticoside, a triterpenoid saponin and trisaccharide derivative of asiatic acid, exerts antibiofilm effects through the core aglycone asiatic acid, which disrupts bacterial membrane potential, inhibits autoinducer synthesis, and downregulates biofilm-associated genes including lasI, rhlI, and pelB. The trisaccharide moieties enhance aqueous solubility relative to the free aglycone. Carvacrol and thymol act through membrane permeabilization and QS disruption.
Tannins, including tannic acid and epigallocatechin gallate (EGCG), suppress quorum sensing by reducing AHL production, degrade extracellular polysaccharides to disrupt biofilm architecture, and inhibit bacterial adhesion.

5.2. Examples

Among the most pharmacologically significant members of this compound family are quorum-sensing disruptors and EPS-modulating agents. Figure 2 illustrates how flavonoids, phenols, terpenoids, and tannins target bacterial cell membranes, inhibit essential enzymes, and generate reactive oxygen species (ROS).
Figure 2. Mechanisms of action of four major classes of plant secondary metabolites against bacterial biofilms. The figure illustrates how flavonoids, phenols, terpenoids, and tannins disrupt biofilm formation through inhibition of bacterial adhesion, disruption of quorum sensing, degradation of the EPS matrix, damage to bacterial cell membranes, and inhibition of bacterial motility. Arrows indicate the site and direction of each inhibitory action on the biofilm life cycle; the central dotted cycle represents the stages of biofilm development targeted by the metabolites; color coding differentiates flavonoids, phenols, terpenoids, and tannins, and the inhibition symbol (⊥) marks each pathway blocked by the respective compound class.

5.2.1. Furanones (Quorum-Sensing Inhibitors)

Furanones are naturally occurring compounds derived from marine algae, notably Delisea pulchra. They disrupt inter-bacterial communication by competing with signal molecules at QS receptor sites, inhibiting quorum sensing and preventing biofilm formation. Furanone application results in enhanced antibiotic efficacy against biofilm-associated infections and reduced virulence gene expression [62].

5.2.2. Phenolic Compounds: Gallic Acid

Gallic acid and related phenolic compounds inhibit biofilm formation primarily by disrupting the biofilm EPS matrix, thereby preventing bacterial attachment to surfaces. This disruption renders bacteria more susceptible to both antimicrobial agents and host immune defenses. Susceptible species include Salmonella enterica and Escherichia coli.

5.2.3. Terpenoid Alcohol (Phytol)

Phytol is a terpenoid alcohol present in the leaves of Piper betle with documented anti-quorum sensing and antibiofilm activity. The compound inhibits the capacity of Serratia marcescens to synthesize virulence factors such as lipase and prodigiosin, reducing biofilm synthesis through downregulation of QS-controlling genes and subsequent suppression of EPS production and bacterial motility [63,64].

5.3. Case Studies

Owing to their enhanced resistance to antimicrobial agents, biofilms—bacterial com-munities adhering to surfaces—pose a major challenge in both industrial and clinical settings. Numerous substances with antibiofilm potential have been identified in the scientific literature; two representative examples are presented below.

5.3.1. Cefixime and Carvacrol Against Escherichia coli Biofilms

A study published in BMC Microbiology investigated the effects of carvacrol, a monoterpenoid phenol, on biofilms produced by Escherichia coli, either alone or in combination with the antibiotic cefixime. Sub-MICs of both agents were evaluated using a microtiter plate biofilm assay. Both carvacrol and cefixime demonstrated significant antibiofilm activity at the MIC level, and scanning electron microscopy (SEM) confirmed structural disruption of the biofilm matrix. The combination demonstrated enhanced biofilm-disrupting activity, increasing pathogen susceptibility to antimicrobial intervention [65].

5.3.2. Antibiofilm Activity of Oregano-Derived Compounds Combined with Biogenic Silver Nanoparticles Against Klebsiella pneumoniae

A study published in Frontiers in Microbiology investigated the antibiofilm activity of biogenic silver nanoparticles (AgNPs) synthesized using Fusarium oxysporum extracts against carbapenem-resistant Klebsiella pneumoniae. Biofilm formation and metabolic activity were quantified using crystal violet staining and MTT assays, respectively. The results demonstrated a strong synergistic inhibition of biofilm formation and bacterial metabolic activity, suggesting that biogenic AgNP-based formulations may represent a viable therapeutic approach for carbapenem-resistant K. pneumoniae infections [66].

5.4. Medical Applications

The clinical application of plant secondary metabolites extends beyond their direct antimicrobial activity to encompass their integration into medical-grade formulations designed to prevent and treat device-associated infections and chronic wound biofilms. While conventional antibiotic coatings on implants suffer from rapid depletion and resistance selection, secondary metabolite-based bioactive films offer a distinct advantage through their multi-target mechanisms of action and reduced propensity for resistance development. The novelty of their application in medicine lies in this ability to simultaneously disrupt biofilm formation, modulate host immune responses, and potentiate the activity of co-administered antibiotics—pharmacological advantages not achievable through conventional monotherapy approaches [67].

5.4.1. Medical Device and Implant Applications

The functionalization of implants and medical devices with antimicrobial films containing plant secondary metabolites represents a clinically significant strategy for reducing nosocomial infections. Secondary metabolite-incorporated films provide sustained release of bioactive compounds at the implant surface, maintaining local antimicrobial concentrations without systemic toxicity. Protein-based films capable of targeted antibiotic delivery and antifouling activity have been synthesized using natural compounds, demonstrating reduced biofilm formation on implant surfaces [67].

5.4.2. Industrial and Packaging Applications

Antimicrobial films incorporating plant-derived secondary metabolites are applied in the food industry to extend product shelf life by inhibiting microbial spoilage. Antimicrobial coatings may be deposited on polymer surfaces or embedded within the polymer matrix. Surface deposition methods such as electrospinning and spray coating are particularly suitable for heat-sensitive antimicrobials, preserving bulk packaging material properties [68].

5.4.3. Environmental Applications

Antibacterial films have been developed and applied in high-contact environmental surfaces—including public transport vehicles and water treatment facilities—to reduce pathogen transmission. The FLEXPOL project, for example, developed antibacterial adhesive films for public transport applications, demonstrating meaningful reductions in bacterial contamination [69].

6. Antibacterial Activities

Antibacterial activity refers to the capacity to inhibit or eliminate bacterial growth and infection. This property is of fundamental importance in drug discovery, particularly in the context of multidrug-resistant bacterial infections. A study published in Evidence-Based Complementary and Alternative Medicine demonstrated that ethanolic extracts of Rhus javanica leaves inhibit the growth of methicillin-resistant Staphylococcus aureus (MRSA) at concentrations of 0.05–0.2 mg/mL, with additional suppression of biofilm formation, supporting its value as a candidate antimicrobial against MRSA infections [70].

6.1. Mechanism of Action

Table 2 presents the antibacterial mechanisms of action of flavonoids, phenolic compounds, terpenoids, and tannins against drug-sensitive and drug-resistant bacterial strains, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, MRSA, and Streptococcus mutans.
Table 2. Antibacterial mechanisms of plant secondary metabolites against drug-sensitive and drug-resistant bacterial pathogens, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, methicillin-resistant S. aureus (MRSA), and Streptococcus mutans.

6.2. Examples

6.2.1. Alkaloid: Berberine

Berberine is a plant-derived isoquinoline alkaloid with documented activity against a broad spectrum of microorganisms. A study in Infection and Drug Resistance demonstrated that berberine effectively reduced MRSA counts by 2 log CFU/mL within 24 h, disrupting bacterial cell wall and membrane integrity and producing altered cellular morphology consistent with bactericidal activity [98].

6.2.2. Flavonoid: Quercetin

Quercetin is a widely distributed flavonoid present in numerous fruits and vegetables. Studies published in Molecules have documented broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria, as well as antifungal and antiviral properties. The antimicrobial mechanisms include disruption of bacterial cell membrane architecture, alteration of membrane permeability, inhibition of nucleic acid and protein synthesis, suppression of virulence factor production, and prevention of biofilm formation [99].

6.2.3. Alkaloid: Daturine

Daturine is an alkaloid isolated from Datura stramonium that demonstrates significant antibacterial activity. A study in the African Journal of Traditional, Complementary and Alternative Medicines reported that ethanol extracts containing daturine showed significant growth inhibition against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Salmonella typhi, and Klebsiella pneumoniae [100].

6.3. Case Studies

6.3.1. Carvacrol Versus Carbapenemase-Producing K. pneumoniae

Carvacrol demonstrates effective antibacterial activity against carbapenemase-producing Klebsiella pneumoniae, a clinically significant multidrug-resistant organism. In vitro studies revealed low minimum inhibitory concentrations (MICs), and time-kill assays confirmed bactericidal activity within four hours. In a murine infection model, carvacrol significantly increased survival rates and reduced bacterial burden in peritoneal lavage fluid, while also restoring suppressed platelet counts—indicating both antibacterial and immunomodulatory effects [101].

6.3.2. WLBU2 Antimicrobial Peptide Against Biofilms of Pseudomonas aeruginosa

WLBU2 is a synthetic antimicrobial peptide demonstrating promising activity against drug-resistant Pseudomonas aeruginosa biofilms. In vitro studies determined a planktonic MIC of 8–16 µg/mL and a minimum biofilm inhibitory concentration (MBIC) of 64 µg/mL, achieving greater than 50% biofilm destruction. In vivo murine studies confirmed dose-dependent biofilm inhibition (33–67%) at concentrations of 1/4× to 1× MIC. The capacity of WLBU2 to simultaneously target both planktonic and biofilm-associated bacteria at low concentrations reduces the likelihood of resistance development, representing a promising approach for chronic infections including cystic fibrosis and medical device-associated biofilms [102].

6.4. Applications

6.4.1. Clinical Use

To promote healing and prevent infection, secondary metabolites with antibacterial activity have been incorporated into wound dressings. For instance, chitosan-based wound dressings incorporating natural compounds have demonstrated enhanced antibacterial properties and accelerated wound healing [103].

6.4.2. Food Storage

Owing to their potent antibacterial activity, plant-derived secondary metabolites such as polyphenols are used in the food industry to preserve foods safely and extend shelf life [104].

6.5. Material Coatings

Polymer coatings incorporating antibacterial secondary metabolites are used to reduce contamination and material deterioration by inhibiting microbial growth [105].

6.6. Agriculture

Antibacterial secondary metabolites also function as natural insecticides and are integral to sustainable agricultural practice. Produced by fungi and bacteria, these metabolites protect plants from infection and insect invasion, thereby reducing reliance on synthetic pesticides. For example, secondary metabolites produced by certain bacteria have been shown to act as effective biocontrol agents [106].

7. Synergy Between Secondary Metabolites

Figure 3 depicts the combined mechanisms by which phytochemicals enhance antibiotic efficacy, including increased membrane permeability, efflux pump inhibition, biofilm matrix disruption, quorum sensing inhibition, and enzyme inhibition (e.g., β-lactamase).
Figure 3. Synergistic effects of plant secondary metabolites with conventional antibiotics. This figure depicts the combined mechanisms by which phytochemicals enhance antibiotic efficacy, including increased membrane permeability, efflux pump inhibition, biofilm matrix disruption, quorum sensing inhibition, and enzyme inhibition (e.g., β-lactamase). Arrows denote the direction of the synergistic interaction between each phytochemical and its co-administered antibiotic; the inhibition symbol (⊥) marks blocked bacterial defense targets; color coding distinguishes the antibiotic, the phytochemical, and the bacterial target structures depicted in this schematic illustration.

7.1. Lignans and Alkaloids in Magnolia officinalis

Lignans such as magnolol and honokiol from Magnolia officinalis exert antibacterial activity through inhibition of DNA gyrase and disruption of bacterial cell wall integrity. Alkaloids in the same extract enhance membrane permeability, augmenting antibiotic effectiveness. Extracts of M. officinalis have been reported to synergize with oxacillin, significantly reducing its MIC against MRSA and supporting dose reduction strategies to limit adverse effects [107].

7.1.1. Polyphenols in Grape Pomace

Polyphenols, including catechin, epicatechin, and procyanidin from grape pomace, enhance antibacterial activity through efflux pump inhibition (increasing antibiotic intracellular residence time), interference with biofilm formation, and generation of oxidative stress via ROS production. These compounds demonstrated significant synergism with tetracycline against Staphylococcus aureus and Escherichia coli, overcoming antibiotic resistance [108].

7.1.2. Tannins, Flavonoids, and Polyphenols in Triphala

Tannins, flavonoids, and polyphenols in Triphala exhibit complementary antibacterial mechanisms: tannins bind to bacterial proteins and membrane structures; polyphenols induce oxidative damage and inhibit essential enzymes; flavonoids induce oxidative stress on bacterial membrane structures. Triphala augments the efficacy of oxacillin against MRSA and gentamicin against Gram-negative bacteria, significantly reducing MIC levels and suppressing resistance development [109].

7.1.3. Terpenoids in Lamiaceae Plant Extracts

Monoterpenes and sesquiterpenes from Lamiaceae plants increase bacterial membrane permeability, alter ion channel function to produce osmotic imbalance, and raise antibiotic penetration rates, thereby amplifying bactericidal activity. Plant terpenoids from the Lamiaceae family demonstrate synergism with streptomycin, producing enhanced antibacterial efficacy against multiple bacterial species while preventing resistance development [110].

7.2. Limitations and Challenges

The physicochemical instability of many secondary metabolites leads to degradation and loss of bioactivity under conditions of elevated temperature, altered pH, and light exposure [111]. Poor aqueous solubility and low gastrointestinal permeability result in inadequate oral bioavailability, limiting therapeutic efficacy; nanotechnology-based co-delivery systems offer viable solutions [112]. At elevated concentrations, some secondary metabolites demonstrate toxicity to mammalian cells and ecological systems, underscoring the need for rigorous toxicological evaluation [113]. Repeated administration of antimicrobial secondary metabolites carries the risk of resistance development, necessitating ongoing discovery of novel compounds and rational combination strategies [114]. Extraction and purification processes are technically complex and frequently require specialized equipment, increasing the cost of large-scale production [115]. Industrial production may generate environmental waste and involve toxic solvents; adoption of green chemistry and clean production technologies is essential to address this concern (Figure 4) [114].
Figure 4. Delivery strategies for overcoming the limitations of plant secondary metabolites. A schematic outline of nanotechnological approaches including encapsulation in biodegradable nanoparticles, surface functionalization for targeted delivery, co-delivery with antibiotics, hydrogels for localized release, and stimuli-responsive systems for controlled drug release. Arrows indicate the sequential delivery process from nanocarrier formulation to release at the target site; color coding differentiates the nanoparticle carrier, the encapsulated phytochemical, and the targeting/stimuli-responsive components illustrated in the schematic.

8. Perspective for the Future

8.1. Newer Methods for Drug Discovery

High-throughput screening (HTS) is indispensable for the rapid identification of drug leads from large compound libraries, enabling parallel evaluation of thousands of compounds simultaneously. Phthalimide analogs with potent antileishmanial properties were identified through HTS, demonstrating the utility of this approach for natural product-derived lead discovery [116]. Phenotypic screening, which monitors compound effects on whole cells, provides additional information on compound-network interactions and has successfully identified active compounds against Leishmania species [117].

8.2. Studies Relating to the Structure–Activity Relationship (SAR)

SAR studies are fundamental to understanding the relationship between molecular structure and biological activity. Structural modifications to lead molecules identified through HTS can enhance potency, selectivity, and pharmacokinetic profiles. A well-characterized example involves SAR studies on 6-dialkylaminopyrimidine carboxamides, which identified the structural features critical for antitubercular activity through optimization of an HTS-derived lead compound [118].

8.3. Innovation in the Development of Drug Delivery Systems

Nanoparticle-based drug delivery systems have dramatically advanced the ability to improve bioavailability and achieve controlled, targeted drug release, overcoming key limitations of traditional delivery approaches, including low bioavailability and poor tissue targeting. pH-sensitive nanoparticles designed for tumor microenvironment-responsive drug release have demonstrated improved efficacy and reduced toxicity in combination chemo-immunotherapy models, offering a conceptual framework applicable to the delivery of plant secondary metabolites to infection sites [119,120]. Figure 5 demonstrates the Clinical translation workflow for plant secondary metabolites as next-generation antibiofilm and antimicrobial agents.
Figure 5. Clinical translation workflow for plant secondary metabolites as next-generation antibiofilm and antimicrobial agents.

8.4. Exploring Underexplored Biological Sources

The exploration of underutilized biological sources—including extremophilic microorganisms, deep-sea sediment bacteria, endophytic fungi, and cryophilic species—has generated growing enthusiasm as a strategy for discovering structurally novel secondary metabolites with antimicrobial potential. Extremophiles have evolved unique biochemical pathways to survive under conditions of extreme temperature, salinity, or pH, and these adaptations frequently yield chemically distinctive natural products with medicinal applications [121].
However, the current state of evidence in this field must be critically appraised. While the identification of a novel furopyrimidine from the endolithic actinomycete Actinomadura sp. AL2—exhibiting potent in vitro antibacterial activity—represents a compelling proof of concept [122], the majority of compounds isolated from extremophilic sources have been evaluated only in preliminary in vitro systems. Systematic in vivo pharmacokinetic, pharmacodynamic, and toxicological data for these compounds are largely absent. Claims regarding the translational potential of extremophile-derived antibiotics must therefore be made with appropriate scientific caution and are currently largely hypothetical pending rigorous experimental validation.
Future work in this area requires standardized in vitro–in vivo correlation studies, validated animal infection models, and structured translational evaluation pipelines before extremophile-derived compounds can be considered viable drug development candidates. Table 3 represents the plant sources of major secondary metabolite classes with antibacterial and antibiofilm activity.
Table 3. Representative plant sources of major secondary metabolite classes with antibacterial and antibiofilm activity.

9. Conclusions

This review has critically examined the antibacterial and antibiofilm pharmacology of five major classes of plant secondary metabolites—flavonoids, phenolic acids, tannins, terpenoids, and alkaloids—with particular emphasis on their mechanistic diversity, synergistic potential with conventional antibiotics, and translational relevance in the context of antibiotic resistance and biofilm-associated infections.
Among the compounds reviewed, several have demonstrated clinically meaningful pharmacological profiles. Quercetin and epigallocatechin gallate (EGCG) exhibit potent multi-target antibiofilm activity, disrupting quorum sensing, degrading EPS, and inhibiting bacterial adhesion across clinically relevant pathogens including MRSA and Pseudomonas aeruginosa. Carvacrol and thymol demonstrate direct bactericidal and antibiofilm efficacy through membrane permeabilization and QS disruption, with carvacrol validated in animal infection models. Betulinic acid exerts antibacterial activity through membrane disruption and DNA gyrase inhibition, with emerging evidence of synergistic efficacy in combination with β-lactam antibiotics against MRSA. Berberine demonstrated efficacy against clinical MRSA isolates. Tannic acid and procyanidins suppress biofilm formation through AHL inhibition and EPS degradation.
Nevertheless, substantial translational barriers remain. Poor oral bioavailability, physicochemical instability, dose-dependent cytotoxicity, and the potential for resistance development are challenges that must be systematically addressed before clinical application. Based on the evidence reviewed herein, the following five specific research priorities are proposed:
Priority 1—Molecular target identification and mechanistic resolution: Future research should employ advanced structural biology tools—including molecular docking, cryo-electron microscopy, and proteomic target-fishing approaches—to precisely identify the molecular targets of the most pharmacologically active secondary metabolites, particularly among triterpenoids and flavonoids with demonstrated biofilm-disrupting activity. Such target identification is essential for rational SAR-guided structural optimization.
Priority 2—Standardized in vivo biofilm infection models: There is a critical and unmet need to develop and validate standardized in vivo animal models of biofilm-associated infection—including catheter-associated urinary tract infection models, implant biofilm infection models, and chronic wound infection models—that replicate clinically relevant conditions and can serve as pharmacological benchmarks for evaluating secondary metabolites under physiological constraints.
Priority 3—Pharmacokinetic optimization through nanoformulation: Compounds including quercetin, EGCG, and betulinic acid are characterized by poor oral bioavailability and rapid systemic clearance. Systematic nanoencapsulation studies using biodegradable polymeric nanoparticles, lipid nanocarriers, and stimuli-responsive delivery systems are warranted to address these pharmacokinetic limitations and improve target-site drug concentrations.
Priority 4—Systematic synergy mapping against ESKAPE pathogens: Structured combination studies using checkerboard and time-kill assay methodologies should be conducted to systematically map synergistic interactions between plant secondary metabolites and clinically used antibiotics against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacterales species) to identify clinically actionable combination regimens for drug-resistant infections.
Priority 5—Clinical translation through Phase I/II trials: Secondary metabolites with robust preclinical safety and efficacy profiles—including those with validated in vivo antibiofilm activity—should be advanced toward carefully designed early-phase clinical trials focusing on safety, tolerability, pharmacokinetics, and proof-of-concept antibiofilm efficacy in patients with device-associated or chronic wound infections. Standardized clinical endpoints for antibiofilm activity must be developed in parallel.
In summary, plant secondary metabolites—particularly flavonoids, phenolic acids, terpenoids, tannins, and alkaloids—represent a diverse and mechanistically rich source of lead compounds for the development of next-generation antimicrobial and antibiofilm therapeutics. Their multi-target mechanisms of action, combined with demonstrated synergy with existing antibiotics, position them as scientifically compelling candidates for the management of drug-resistant and biofilm-associated infectious diseases. Systematic translational research guided by the priorities outlined above will be essential to realize their clinical potential.

Author Contributions

S.P.: Writing—review and editing, Writing—original draft, Conceptualization; S.B.N.: review and editing; A.K.: Validation and formal analysis; N.S.: Software, review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No data were used for the research described in the article.

Acknowledgments

The authors acknowledge that generative artificial intelligence tools (including language refinement assistants—QuillBot & ChatGPT) were utilized during manuscript preparation solely to assist with grammar and language editing (version: ChatGPT-4, 2025). No manuscript content was generated, and no data were interpreted by AI tools. All figures were created originally by the authors using Illustrae.co (https://illustrator.co/, accessed on 24 June 2026); no figures were reproduced from third-party sources, and no permissions are required. The authors assume complete responsibility for the intellectual content, accuracy, and conclusions presented herein.

Conflicts of Interest

The authors declare no conflicts of interest.

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