Synergistic Multi-Herb Approaches for Reversing Microbial Biofilms in Chronic Infections

Shruti Bijwe, Shreeya Hambarde, Mayuri Randive, Khushi Raikwad, Arpita Bhajipale, Nishant Awandekar, Millind Umekar,

doi:10.5281/zenodo.18213434

Review Paper | Open Access
Volume 03 | Issue 01 | Article Id IJPS/250312664

Synergistic Multi-Herb Approaches for Reversing Microbial Biofilms in Chronic Infections
Shruti Bijwe* Shreeya Hambarde Mayuri Randive Khushi Raikwad Arpita Bhajipale Nishant Awandekar Millind Umekar
Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India-441002

Abstract

Chronic infections are largely sustained by microbial biofilms, complex, multicellular matrices that confer antimicrobial tolerance and immune evasion. Conventional antibiotic regimens fail to eradicate these resilient structures due to limited penetration, metabolic dormancy, and efflux-mediated resistance. In recent years, phytochemicals have emerged as promising anti-biofilm agents through diverse mechanisms, including quorum-sensing inhibition, extracellular polymeric substance (EPS) disruption, and persister-cell eradication. Compounds such as curcumin, berberine, allicin, cinnamaldehyde, and catechins act at sub-inhibitory concentrations to suppress virulence and enhance antibiotic susceptibility. Multi-herb or polyherbal combinations further potentiate efficacy via synergistic interactions, simultaneously targeting quorum sensing, adhesion, and EPS synthesis while minimising resistance risks. Delivery innovations such as herbal nanoparticles, nanofibers, and mucoadhesive gels improve bioavailability, sustained release, and site-specific action against chronic wounds, oral, and urinary tract biofilms. This review synthesises current evidence on synergistic multi-herb strategies and highlights their mechanistic roles in disrupting biofilm integrity, downregulating virulence gene expression, and reactivating persister metabolism. Despite significant in vitro advances, translational challenges persist due to limited standardisation, dose optimisation, and clinical validation. Integrating polyherbal therapeutics with advanced delivery systems represents a novel, multi-targeted approach for combating chronic infections, reducing antibiotic reliance, and supporting host immune resilience. Future research should focus on systematic synergy modelling, pharmacokinetic profiling, and in vivo evaluation to establish safe, effective phytotherapeutic interventions for biofilm-associated diseases.

Keywords

Biofilms; Chronic infections; Phytochemicals; Herbal synergy; Quorum sensing inhibition; EPS disruption; Persister cells; Nanoparticle delivery; Polyherbal formulations; Antimicrobial resistance.

Introduction

Chronic infections persist due to bacterial biofilms, structured communities embedded in an extracellular matrix that shield microbes from host defences and treatments (1). These biofilms affect 65-80% of human infections, like cystic fibrosis and implant-related issues (2). Biofilms cause prolonged inflammation and recurrence, complicating clinical management in wounds, catheters, and dental plaques (3). Antibiotics fail against biofilms due to poor matrix penetration and the slow growth of persister cells (4). Biofilms show up to 1000-fold increased tolerance compared to planktonic cells (5). Efflux pumps and altered metabolism further reduce the efficacy of antibiotics, leading to persistent infections despite high-dose regimens (6). Herbal phytochemicals like berberine, curcumin, quercetin, and baicalin inhibit quorum sensing, adhesion, and EPS production (7). They disrupt biofilms at sub-MIC levels without fostering resistance (8). Compounds such as cryptotanshinone and mangiferin target virulence genes in pathogens like P. aeruginosa and S. aureus (9). Multi-herb combinations enhance efficacy through synergistic mechanisms like QS inhibition plus anti-adhesion (10). They reduce biofilm biomass more than single agents and minimise resistance risks (11). Polyherbal formulations mimic traditional medicine, improving penetration and multitarget action (12). This review assesses the synergistic effects of phytochemicals on biofilm disruption in chronic infections (13). It synthesises mechanisms, efficacy data, and clinical translation potential to guide novel herbal therapies (14).

1.1 Mechanisms of Biofilm Formation

Biofilm formation follows a structured lifecycle (15). Initial attachment of planktonic bacteria to a surface occurs first (16). This progresses to irreversible adhesion and microcolony formation (17). Maturation involves proliferation and EPS production, creating a three-dimensional matrix (18). The cycle concludes with dispersal, where cells revert to planktonic form due to nutrient depletion or signalling (19). Quorum sensing (QS) enables bacterial communication via autoinducer molecules like N-acyl-homoserine lactones (20). QS regulates gene expression based on population density (21). QS triggers EPS production, virulence factors, and biofilm maturation through coordinated collective behaviour (22). It plays a vital role in biofilm architecture and antibiotic tolerance (23). EPS provides structural integrity, adhesion, and protection against antibiotics and host defences. During maturation, EPS production increases to create water channels for nutrient flow and waste removal. Persister cells are dormant, antibiotic-tolerant subpopulations within biofilms. They form in higher numbers during biofilm culture than during planktonic growth. Persister cells contribute to recurrence post-treatment. Biofilms cause 65-80% of chronic infections, including cystic fibrosis and implant-associated osteomyelitis (24).

2. ANTI-BIOFILM MECHANISMS OF HERBS

2.1 QS Inhibition

Herbal compounds like berberine, curcumin, and garlic-derived ajoene block quorum sensing by antagonising autoinducer receptors such as LasR in P. aeruginosa and Agr in S. aureus (25). This disrupts coordinated behaviours essential for biofilm initiation and maturation without killing planktonic cells (26). QS inhibitors from herbs like Rosa rugosa tea polyphenols reduce violacein production in Chromobacterium violaceum reporter strains by over 70% (27).

2.2 EPS Disruption

Phytochemicals such as tannins from Punica granatum and flavonoids from green tea destabilise the EPS matrix by binding polysaccharides and eDNA (28). They reduce biofilm biomass by 50-80% in S. aureus and Candida models(29).

Cranberry proanthocyanidins inhibit EPS synthesis enzymes, creating structural voids that enhance antibiotic penetration (30). Enzyme-mimicking polyphenols from Herba patriniae degrade mature EPS scaffolds (31).

2.3 Persister Cell Eradication

Carvacrol from oregano and thymol penetrate dormant persister cells, disrupting membrane potential and ATP synthesis (32). They achieve 4-5 log reductions in E. coli and P. aeruginosa persisters(33). Alkaloids like sanguinarine from Sanguinaria canadensis target toxin-antitoxin modules, reactivating metabolic pathways in persisters (34). Combined herbal extracts show synergy with antibiotics, eradicating 99% of persisters that survive ampicillin alone (35).

2.4 Gene Expression Modulation

Quercetin and resveratrol downregulate biofilm-associated genes (pel, algD, ica) by 60-90% through histone deacetylase inhibition and sRNA interference (36). Polygonum chinense extracts suppress the ica operon in S. aureus, reducing PIA production essential for adhesion (37). Epigallocatechin gallate modulates global regulators like RpoS, shifting bacteria toward planktonic growth (38).

2.5 Fermentation-Enhanced Bioactive Compounds

Fermented herbal products like kimchi-derived phenolics and Ginkgo biloba extracts increase anti-biofilm potency 2-5 fold via microbial biotransformation (39). Lactic acid fermentation of garlic enhances allicin derivatives that inhibit QS 3x more effectively than fresh extracts (40). Traditional fermented medicines like Tripterygium wilfordii show 80% biofilm reduction in MRSA due to novel isoflavone metabolites (41).

3. SYNERGISTIC MULTI-HERB APPROACHES

3.1 Definition and Concept of Herbal Synergy

Herbal synergy refers to the combined action of multiple plant extracts or phytochemicals that produce therapeutic effects greater than those of individual herbs alone. This synergism may occur through complementary mechanisms such as enhanced bioavailability, multi-target interactions, or improved antimicrobial potency (42). In the context of biofilms, synergy helps target the structurally and functionally diverse layers of microbial communities more effectively than single-herb formulations (43).

3.2 Examples of Herb Combinations Targeting Biofilms

Several multi-herb combinations have shown enhanced antibiofilm effects, such as curcumin + piperine, where piperine increases curcumin’s penetration and activity against EPS-producing bacteria (43). Garlic (allicin) + gingerol-rich extracts demonstrate synergistic inhibition of quorum sensing and bacterial adhesion (44). Combinations like berberine + tea polyphenols also display enhanced biofilm disruption and suppression of virulence pathways (45). These synergistic pairs highlight the potential of multi-herb formulations in overcoming biofilm-related chronic infections.

3.3 Mechanistic Classification: Layer-Wise Biofilm Disruption

Multi-herb synergy can be classified based on the specific biofilm layer or component each herb targets:

EPS Matrix Disruption: phytochemicals such as eugenol and cinnamaldehyde weaken the structural integrity of the EPS layer (48).
Quorum Sensing Inhibition: compounds like curcumin and catechins block signalling pathways, reducing virulence and biofilm maturation (49).
Persister Cell Targeting: alkaloids such as berberine and reserpine exhibit activity against dormant persister cells within biofilms (50).
Immune Modulation: herbs like turmeric, neem, and ashwagandha enhance host immune responses, supporting clearance of chronic infections (51).

Together, these mechanisms demonstrate how multi-herb formulations can comprehensively weaken, disrupt, and eliminate biofilms.

3.4 Advantages Over Single-Herb Therapy

Multi-herb formulations provide several benefits over single-herb approaches, including broader antimicrobial activity, reduced resistance development, and enhanced effects at lower doses (52). Synergistic herb combinations allow simultaneous targeting of multiple biofilm pathways: EPS degradation, quorum-sensing suppression, cell membrane disruption, and immune enhancement, leading to more efficient biofilm eradication (53). Multi-herb strategies also lower toxicity and improve therapeutic safety compared to high-dose monotherapies (54).

4. DELIVERY SYSTEMS FOR ENHANCED EFFICACY

4.1 Nanofiber-Based Herbal Delivery

Nanofiber matrices provide a high surface area and controlled release environment for herbal bioactives, enabling sustained delivery at infection sites. Electrospun nanofibers loaded with phytochemicals such as curcumin, neem extract, or essential oils show improved penetration into biofilm layers and enhanced antimicrobial activity compared to free extracts (51,52). Their porous structure allows deeper diffusion into biofilms, making them highly effective for chronic wound infections.

4.2 Mucoadhesive Gels

Herbal mucoadhesive gels prolong the retention time of phytochemicals on mucosal surfaces such as the oral cavity, nasal mucosa, or vaginal membranes. This extended contact enhances the antibiofilm action of herbs like aloe vera, liquorice, curcumin, and neem, allowing continuous release at the infection site (53). Mucoadhesive polymers such as Carbopol, xanthan gum, and chitosan further enhance penetration through biofilm EPS while improving patient compliance (54).

4.3 Herbal Nanoparticles

Nanoparticle-based herbal formulations—such as curcumin nanoparticles, berberine-loaded chitosan nanoparticles, and silver–herbal hybrid nanoparticles—significantly increase bioavailability and cell uptake of phytochemicals (55). Due to their nanoscale size, these particles can penetrate dense biofilm matrices and disrupt microbial adhesion, quorum sensing, and metabolic pathways more efficiently than conventional extracts (56). Nanoencapsulation also protects unstable herbal compounds from degradation.

4.4 Role in Targeted Biofilm Disruption

Advanced delivery systems enhance targeted action against specific biofilm components. Nanoparticles and nanofibers can be engineered to preferentially bind bacterial surfaces, degrade EPS, or release phytochemicals in response to infection-specific conditions such as pH or enzymes (56). These targeted systems provide multi-layer disruption, EPS breakdown, inhibition of quorum sensing, and eradication of persister cells, making them highly effective for chronic infections (57). Mucoadhesive platforms further localise these effects at mucosal biofilm sites.

5. KEY HERBS WITH MULTI-TARGET ANTI-BIOFILM ACTIVITY

Curcumin

Curcumin inhibits quorum sensing, suppresses EPS matrix synthesis, and increases membrane permeability in Pseudomonas aeruginosa and Staphylococcus aureus (58,59).

Demonstrates synergistic disruption when combined with antibiotics and other herbs.
(60).

Berberine

Berberine interferes with microbial signalling pathways (LuxS, LasR), reducing biofilm thickness and metabolic activity(61).

Shows strong synergy with flavonoids, curcumin, and antibiotics, improving penetration into mature biofilms(62).

Allicin (Garlic-derived)

Allicin penetrates microbial cell walls, disrupts thiol-containing enzymes, and inhibits EPS formation(63).

Effective against multi-drug-resistant (MDR) staphylococcal and fungal biofilms(64).

Cinnamaldehyde

Damages biofilm architecture by breaking hydrogen-bond networks and downregulating adhesion genes (fimA, curli)(65).

Inhibits quorum–sensing–regulated virulence factors in gram-negative pathogens(70).

Tea Polyphenols (EGCG & Catechins)

EGCG reduces cell adhesion, inhibits amyloid-like fibrils in the biofilm matrix, and potentiates antibiotic uptake(71).

Prevents initial colonisation and reduces multidrug efflux pump activity in biofilm-forming bacteria(72).

Liquorice Flavonoids (Glycyrrhizin, Licochalcone A)

Licochalcone A targets metabolic pathways involved in EPS synthesis and biofilm maturation(73).

Glycyrrhizin destabilises membrane integrity and downregulates persister-cell formation.
(74).

Other Emerging Phytochemicals

Boswellic acids

Reduce oxidative stress and inhibit EPS synthesis in chronic inflammatory biofilms(75).

Thymol and Carvacrol (from thyme & oregano)

Causes rapid membrane depolarisation and collapse of metabolic activity inside mature biofilms(76).

Baicalin (Scutellaria baicalensis)

Acts as a quorum-quenching agent and enhances antibiotic sensitivity(77).

6. RESEARCH GAPS AND FUTURE DIRECTIONS

Lack of Standardised Anti-Biofilm Assays

Current studies rely on variable in vitro methods (microtiter plates, crystal violet, CLSM), limiting comparability across laboratories(78).

No universal guidelines exist for evaluating herbal anti-biofilm activity, leading to inconsistent reporting of MIC, MBIC, and MBEC values(79).

Need for In Vivo and Clinical Studies

Most evidence for herbal anti-biofilm effects comes from in vitro models; animal models and human trials remain limited(80).

Complex host–immune interactions in chronic infections cannot be captured in laboratory biofilm models alone(81).

Optimisation of Synergistic Multi-Herb Combinations

Few studies systematically evaluate dose response, ratio optimisation, or pharmacokinetic compatibility of combined herbs.

Synergy is often reported without mechanistic integration (quorum sensing + EPS inhibition + membrane disruption)(82).

Integration with Conventional Therapy

Combining phytochemicals with antibiotics shows promise, but standardised combinational protocols and safety profiles are underdeveloped(84).

Herb drug interactions, especially CYP-mediated ones, require detailed investigation before clinical translation.

Potential Translational Applications

Advanced delivery systems (nanogels, mucoadhesive systems, nanoparticles) require regulatory evaluation for herbal formulations.

Multi-targeted herbal therapeutics could be integrated into personalised medicine approaches for chronic infections(83).

Table 1. Documented Multi-Herb Combinations Showing Synergistic Anti-Biofilm Effects

Herb Combination	Synergistic Mechanism	Biofilm Type Targeted	Study Outcome	Reference
Curcumin + Berberine	QS inhibition + membrane damage	P. aeruginosa	2–3× higher biofilm reduction vs. single herbs	(84)
Garlic + Ginger	EPS degradation + virulence inhibition	Mixed oral biofilms	Significant reduction in adhesion	(85)
Green tea polyphenols + Liquorice	Adhesion inhibition + anti-inflammatory	Dental plaque	Enhanced inhibition of biofilm biomass	(86)
Cinnamaldehyde + Eugenol	QS disruption + membrane permeability	S. mutans	Reduction in EPS and acidogenicity	(87)
Turmeric + Neem	Anti-inflammatory + antimicrobial synergy	Wound biofilms	Faster wound healing and biofilm control	(88)

Table 2. Herbal Delivery Systems and Their Effectiveness Against Biofilms

Delivery System	Herbal Extract/ Compound	Target Site	Improvement in Efficacy	Reference
Nanofiber patch	Curcumin	Chronic wound biofilms	Sustained release, deeper penetration	(89)
Mucoadhesive gel	Licorice extract	Oral biofilms	Improved retention, reduced inflammation	(90)
Herbal nanoparticles	Berberine NPs	Multi-species biofilms	Enhanced 2× penetration into EPS	(91)
Nanoemulsion	Cinnamaldehyde	Dental plaque	Increased stability & QS inhibition	(92)
Hydrogel	Green tea catechins	UTI biofilms	Controlled delivery, reduced recurrence	(93)

7. CONCLUSION

Multi-herb formulations offer a promising approach for overcoming biofilm-associated chronic infections by simultaneously targeting multiple microbial pathways.

Evidence indicates that combining herbs enhances antibiofilm efficacy through synergistic effects, enabling EPS degradation, quorum-sensing inhibition, reduced bacterial adhesion, and enhanced immune modulation.

Multi-herb synergy provides multi-layered biofilm disruption, including targeting persister cells, inhibiting virulence gene expression, and destabilising microbial membrane integrity.

Herbal combinations also promote host tissue repair, anti-inflammatory responses, and modulation of oxidative stress mechanisms not achieved by conventional antibiotics alone.

Integrating multi-herb strategies with advanced delivery systems (nanogels, nanoparticles, mucoadhesive gels) may significantly improve therapeutic outcomes in chronic wounds, oral infections, UTIs, and respiratory biofilm infections.

These approaches can reduce antibiotic dependence, lower antimicrobial resistance, and serve as safer, multi-target alternatives for long-term management of persistent infection.

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