(March, 2015)


Biofilms are gelatinous masses of microorganisms capable of attaching to virtually any surface. According to the NIH, they factor into nearly 80% of all bacterial infections [Schachter, 2003] and are inherently resistant to antibiotics. Biofilms are what keep wounds from healing, and bladder infections recurring. They may also be why lyme disease lingers. Biofilms are at the heart (and lung) of bacterial pneumonia, and are the death of cystic fibrosis kids and burn patients. Biofilms cause tooth decay, gum disease, sinusitis, ear infections, and Legionnaires’ disease. Biofilms glom onto medical devices (e.g., heart valves, catheters, joint replacements) where they are deadly, or difficult to eradicate. Biofilms plague hospitals, and contribute greatly to our health care burden. [Hall-Stoodley et al., 2004]

Biofilms are also good for us. They line the digestive tract, especially the lower intestines, and the skin. Healthy biofilms contain many different species of bacteria working together to benefit humans. Many trillions of organisms protect us from pathogens and toxins, help boost our immune defenses, keep our plumbing working, steer us away from obesity, and may even make us think and feel better [Pollan, 2013; Rose, 2011]. An imbalance of bacteria in the gut – particularly from antibiotic usage, stress, or lack of fiber in the diet – leaves us susceptible to disease.

There are likely a number of stealthy biofilms that adversely affect the body in unknown ways. The list may include fetal development, autism, depression, chronic fatigue, Lyme disease, cognitive impairment, etc. [Janossy, 2015] Chronic Lyme disease may play a role in the development of dementia and Alzheimer’s. [McDonald, 2012] Many stealthy infectious agents have been identified (e.g., Borrellia, Mycoplasma, Bartonella, Babesia, Rickettsia), but some are still unknown or poorly understood. Chronic inflammation from biofilm infection can lead to cancer, cardiovascular disease, dementia, and other debilitating conditions. [Esser et al., 2015]

Recently, new anti-biofilm agents have been developed as adjuncts or alternatives to classical antibiotic treatment. Many of these novel agents show “resistance” to the emergence of antimicrobial resistance, and even enhance the activity of conventional antibiotics. Anti-biofilm substances may be synergistic with other antimicrobials to overcome persistent infectious threats. [Wu et al., 2004]  The following is a quick review of many of the natural anti-biofilm agents currently under study.

Biofilm-Disrupting Enzymes

Enzymes, like DNase I, α-amylase and DspB are biofilm-dispersing agents that degrade the biofilm matrix, permitting increased penetration of antibiotics. DNase I cleavage of extracellular DNA leads to alterations in biofilm architecture, which permits increased antibiotic penetration. [Tetz et al., 2009] A DNA-dissolving drug (Pulmozyme) has been used in cystic fibrosis patients to help disrupt the biofilm. α-amylase is a proven anti-biofilm agent against Staphylococcus aureus, Vibrio cholerae and Pseudomonas aeruginosa, not only inhibiting biofilm formation, but also degrading preformed mature biofilms [Kalpana et al., 2012]. DspB is a soluble β-N-acetylglucosaminidase with broad-spectrum activity to dissolve the biofilm matrix, and shows synergy with other antimicrobials [Darouiche et al., 2009].

Proteolytic enzymes like serrapeptase help the body break down protein involved in inflammation and mucous. It may also help disrupt the outer layers of biofilms and uncover hidden microbes.

Unfortunately, the high cost of industrial enzyme production makes their large-scale application as anti-biofilm agents unfeasible. [Sun et al., 2013]

Bacteriophages are viruses that produce a number of enzymes that negate the protection afforded by biofilms. Phages degrade the biofilm matrix and lyse bacteria, while leaving friendly bacteria unharmed. Phage modification of biofilm architecture also increases susceptibility to antibiotics. However, phage-resistant bacteria can evolve rapidly. [Sun et al., 2013]

Quorum-Sensing Inhibitors

Quorum-Sensing (QS) is a form of communication bacteria use to cooperatively build biofilm communities. Most bacteria produce QS signals, as well as QS inhibitors. Usnic acid, a lichen metabolite, possesses inhibitory activity against bacterial and fungal biofilms via QS interference. QS inhibitors can increase the susceptibility of biofilms to antibiotics. QS Inhibitors are generally regarded as safe in humans. [Sun et al., 2013]

Garlic inhibits the expression of several genes that control bacterial QS. The star in garlic’s arsenal is ajoene, the sulfur-containing compound produced when garlic is crushed. Ajoene inhibits production of rhamnolipid, which shields biofilms from white blood cells. Over 90% of biofilm bacteria were killed with a combination of ajoene and the antibiotic tobramycin. Garlic also has anti-viral, anti-fungal, and anti-protozoal properties, and benefits the cardiovascular and immune systems. [Jakobsen et al., 2012] These sulfur compounds from garlic quickly lose their activity upon exposure to oxygen. A willow bark extract, hamamelitannin, also inhibits QS. [Morgan, 2015]


The anticancer, antioxidant, and anti-inflammatory effects of flavonoids are well established. Yet, their biofilm disrupting function is practically unknown. Flavonoids appear to suppress the formation of biofilms via a non-specific QS inhibition [Vikram et al., 2010]. The flavonoid phloretin inhibited biofilm formation in E. coli O157:H7, and ameliorated colon inflammation in rats without harming beneficial biofilms [Lee et.al., 2011]. Naturally occurring flavanols in cocoa may reverse memory decline significantly. [Brickman, et al., 2014] Their ability to inhibit QS might provide a clue for their action.

The anti-aging antioxidant resveratrol, associated with red wine, is produced by plants when under attack by pathogens. Resveratrol demonstrated significant antimicrobial properties on periodontal pathogens [O’Connor et al., 2011]

Cranberry has a reputation for keeping bacteria from sticking to surfaces. The red pigments in cranberries have been shown to inhibit biofilm formation. These proanthocyanidins [PACs] have been reported to possess antimicrobial, anti-adhesion, antioxidant, and anti-inflammatory properties. [Bodet et al., 2006] They prevent the attachment of pathogens to host tissues, and can inhibit the formation of biofilms in the mouth and urinary tract. [Labrecque et al., 2006] Cranberry PACs stopped the gum disease pathogen, Porphyromonas gingivitis, from adhering and forming biofilm, which markedly reduced its invasiveness. [La et al., 2010] These unique PACs also prevented adherence and biofilm formation by Candida albicans, the causative agent of thrush and yeast infections. [Feldman et al., 2012]  Cranberry juice extract, at low micromolar levels, inhibited tissue-destroying enzymes made by bacteria [La et al., 2010] and humans. [Bodet et al., 2007] Cranberry PACs also prevented dental plaque, by inhibiting biofilm-forming enzymes, [Steinberg et al., 2004] and keeping bacteria from aggregating. [Weiss et al., 1998; Yamanaka et al., 2004] Daily use of a cranberry-containing mouthwash for 6 weeks significantly reduced levels of mutans streptococci in human saliva. [Weiss et al., 2004] The anti-adhesive benefits of cranberry for urinary tract infections may be substantially increased by increasing the alkalinity of urine (https://thescienceofnutritiondotnet.wordpress.com/2015/07/17/beat-urinary-tract-infections-with-nutrition/).

Chlorogenic acids (CGA), largely from coffee, are cinnamic acid derivatives with important antioxidant and anti-inflammatory activities. [Farah et al., 2008] In vitro antibacterial and anti-biofilm activities of chlorogenic acid against clinical isolates of Stenotrophomonas maltophilia resistant to trimethoprim/sulfamethoxazole (TMP/SMX) was investigated. The MIC and MBC values ranged from 8 to 32 μg/mL. In vitro antibiofilm testing showed a 4-fold reduction in biofilm viability at 4x MIC. [Karunanidhi et al., 2012]

Boswellic acids are pentacyclic triterpenes, produced in plants belonging to the genus Boswellia, with potent anti-biofilm properties. Acetyl-11-keto-β-boswellic acid, which exhibited the most potent antibacterial activity, was effective against all 112 pathogenic gram positive bacteria tested (MIC range, 2-8 μg/ml). It inhibited biofilms formed by S. aureus and S. epidermidis, and could also disrupt preexisting biofilms. Disruption of bacterial membranes is the likely mode of action. [Raja et al., 2011]

The leaf extract of Pongamia pinnata showed significant antibiofilm activity [Karlapudi et al., 2012]. The antimicrobial activity of the plant extract is attributed to the presence of phenolic compounds, such as alkaloids, flavonoids, terpenoids and polyacetylenes. [Shan et al., 2007]

Five Indonesian medical plant extracts were shown to inhibit Pseudomonas aeruginosa and Staphylococcus aureus biofilm formation at concentrations as low as 0.12 mg/mL. [Pratiwi et al., 2015]

Wheat bran extract exhibits anti-biofilm activity, inhibiting biofilm formation and destroying pre-formed S. aureus biofilm in dairy cows with mastitis. [González-Ortiz et al., 2014]

Farnesol and xylitol were shown to possess antibiofilm and antibacterial effects when used in root canal irrigants. [Alves et al., 2013] Xylitol is a low-carb sweetener found in toothpaste and diet sodas. When bacteria incorporate xylitol into the biofilm, it makes for a flimsy structure. [Morgan, 2015]

Aspirin and many other naturally-occurring salicylates have been shown to inhibit the macromolecules that make up the biofilm matrix [Domenico et al, 1990; Muller et al., 1998]. Salicylates are produced by many plants in response to infection.

Pro-oxidants can also be effective against biofilms. Oxidative agents are microbicidal, and offer possibilities for reducing the pathogenic activities of biofilms, especially those with an anaerobic component. In one study, 85% improvement was seen among 66 chronic Lyme disease patients with hyperbaric oxygen therapy, together with antibiotics. [Huang et al., 2014] Oxygen-supercharged Kaqun water, which has exhibited anticancer properties, may also prove useful. In contrast, nitric oxide, a signaling molecule involved in the immune system, promotes biofilm formation. [Plate & Marietta, 2012]

Fatty Acid Inhibitors

Several Salvia (Sage) species widely used as spices were evaluated for their antimicrobial activities, including their anti-adhesive and anti-biofilm effects. Salvia triloba extract demonstrated significant bacteriocidal activity against MRSA. Its volatile oil was active against all tested microorganisms except P. aeruginosa. S. triloba extract and volatile oil were active against biofilms, demonstrating anti-adhesion and anti-biofilm activities, respectively. The antimicrobial activities of other Salvia species were negligible. [Al-Bakri et al., 2010]

Short- and medium-chain fatty acids exhibit antimicrobial activity. Formic, capric, and lauric acids are broadly inhibitory for bacteria. Undecylenic acid is another medium chain fatty acid known for its anti-biofilm ability – including the disruption of troubling biofilms of Candida albicans. [McLain et al., 2000] These fatty acid inhibitors contribute to the formation and interaction of species within biofilms. [Huang et al., 2011]

Bacterial Anti-biofilm Inhibitors

Not surprisingly, bacteria compete with one another for turf. Certain substances on the surface of one bacteria work to inhibit biofilms from another. Extracellular polysaccharides (EPS)  are the essential building blocks for the biofilm matrix of most microorganisms. Thus, EPS is the stuff of biofilms, but can also inhibit their neighbors’ biofilms, from initial adhesion, dispersion, cell to cell communication, to matrix degradation. [Rendueles et al.,2013]

One example of this EPS anti-biofilm activity is in Actinobacillus pleuropneumoniae serotype 5. The EPS from these bacteria inhibits cell-to-cell and cell-to-surface interactions of other bacteria, preventing them from forming or maintaining biofilms. This is one of a growing number of natural bacterial polysaccharides that exhibit broad-spectrum, non-biocidal anti-biofilm activity. [Karwacki et al., 2013]

Numerous bacteria produce anti-biofilm agents. Extracts of a coral-associated bacteria induced a reduction in S. aureus and Serratia marcescens biofilm formation. A novel natural product, 4-phenylbutanoic acid, from the marine bacterium Bacillus pumilus, shows inhibitory activity against biofilms from a broad range of bacteria. [Nithya et al., 2011] Ethyl acetate extracts of the bacterium, Bacillus firmus—a coral-associated bacterium–show antibiofilm activity against biofilms formed by multidrug resistant S. aureus. [Gowrishankar et al., 2012]

Streptococcus salivarius, a non-biofilm, harmless inhabitant of the human mouth, uses two enzymes to inhibit the formation of dental biofilms, otherwise known as plaque. These enzymes were identified as fructosyltransferase (FTF) and exo-beta-d-fructosidase (FruA), which affected a decrease in EPS production. The large quantities of FruA that S. salivarius produces may play an important role in microbial interactions for sucrose-dependent biofilm formation in the mouth. [Ogawa et al., 2011]

Minerals that Affect Biofilm

Many enzymes in the body are metallo-enzymes that rely on iron, zinc, selenium, manganese, magnesium  and other minerals for activity. Toxic heavy metals (mercury, lead, cadmium) can displace the metal component of these metallo-enzymes and render them ineffective or non-functional. Some of these enzymes (e.g., SOD, catalase, glutathione reductase) play key roles in our antioxidant defenses. Toxic metal elimination and good mineral nutrition from organically-grown foods and dietary supplements can enhance our immune capabilities substantially to reduce the risk of infection.

Silver is an important antimicrobial agent used as a coating to reduce bacterial adhesion to biomaterials and prevent infections. Silver ions increase bacterial membrane permeability, induce de-energization of cells, leakage of cellular content, and disruption DNA replication. [Marambio-Jones & Hoek, 2010] Many studies support an anti-biofilm component of silver. However, a recent study suggests that silver may indirectly promote bacterial adhesion [Carvalho et al., 2013].

Iron promotes EPS production and biofilm formation in many pathogenic, biofilm-producing bacteria. By tying up iron, lactoferrin could conceivably show anti-biofilm activity. Lactoferrin shows powerful anti-candida and anti-bacterial properties. [DePas et al., 2012]

Bismuth is an element in the earth’s crust that has been shown to possess anti-biofilm activity. Bismuth appears to work largely by inhibiting bacterial EPS [Domenico et al., 1991, 1992] via competitive interference with iron metabolism. [Domenico et al., 1996] Interestingly, Pepto-Bismol is comprised of two independent and additive anti-biofilm agents, bismuth and salicylate [Domenico et al, 1991, 1992]. The likely main action of Pepto-Bismol is to dampen overgrowth of biofilm in the gut.

Bismuth is a mild agent, but its potency can be enhanced up to 1000-fold with lipophilic thiols. [Domenico et al., 1997] Some thiols used to potentiate bismuth are naturally-occurring, and some are synthetic. Each possesses a unique antibacterial spectrum that adds to the utility of these novel anti-biofilm compounds. Bismuth-thiols (BTs) have potent, broad spectrum activity, even against antibiotic resistant bacteria.  Additionally BTs prevent and eradicate microbial biofilms at low micromolar concentrations. [Domenico et al., 1999; Folsom et al., 2011] Topical BT administration to infected open fracture wounds potentiated the effect of systemically administered antibiotics, reduced infection rate and bacteria quantity associated with bone and orthopaedic implants. [Penn-Barwell 2015] Microbion Corporation’s lead compound, BisEDT, has been granted FDA Qualified Infectious Disease Product (QIDP) status, and is in Phase 2 clinical studies for treatment of orthopedic wound infections and chronic wounds.

The low toxicity of bismuth makes it quite different than most heavy metals, which weaken immunity and create an environment for unhealthy biofilms. Chelation therapy with EDTA removes many of these heavy metals and shows anti-biofilm effects. Chelating agents show biofilm dispersing qualities because the biofilm matrix is held together largely by minerals like calcium, magnesium, and iron. Phosphate is involved also, to solidify the biofilm structure. EDTA weakens the structure of biofilms to allow the immune system or antibiotics to gain access to the microbes hiding deep within biofilm community.  EDTA may supercharge antibiotics by 1000-fold. [Finnegan & Percival, 2014]

Another metal chelator, N-acetyl-L-cysteine (NAC), at low milligram levels, was found to decrease biofilm formation by a variety of bacteria and reduced the production of EPS matrix, while promoting biofilm disruption [Pézer- Giraldo et al., 1997]. Synergy of NAC with ciprofloxacin was shown against biofilm production and pre-formed mature biofilms from many pathogenic microbes on ureteral stent surfaces. NAC increased ciprofloxacin action by degrading the EPS matrix of biofilms. [El-feky et al., 2009]

A healthy gut maintains healthy biofilm communities that support the absorption of nutrients. Using detox agents like charcoal to mop up certain poisons and toxic metabolites, may conceivably protect the gut biofilm, and ward off pathogenic biofilms. Charcoal shows life-extending effects in laboratory rats.[Frolkis et al., 1989]

Other Modalities that Inhibit Biofilms

Antimicrobial Peptides (AMPs) are cationic, amphipathic substances that are part of the innate immunity in animals, plants, and some microbes. AMPs bind to and disrupt bacterial membranes, and efficiently kill biofilms.  AMPs from sea urchins, sea cucumbers and echinoderms have all been shown to disrupt biofilms. Their drawbacks are a sensitivity to salt, ionic strength, pH and proteolytic activity in body fluids. Synthetic AMPs have recently emerged as attractive anti-biofilm agents. Specifically targeted AMPs (STAMPs) are fusion peptides that target single pathogens, and are relatively stable under a range of physiological conditions. STAMPs can selectively eliminate the biofilm-forming, tooth-decay pathogen Streptococcus mutans from a mixed-species environment. [Sun, 2013]

Low-frequency ultrasound treatment in combination with antibiotics is promising for biofilm removal. [He et al., 2011] Ultrasound facilitates transport of antibiotics across biofilms, and increases sensitivity of biofilm-growing bacteria to antibiotics. [Carmen et al., 2005; Dong et al., 2013] It has been used as a treatment for chronic rhinosinusitis. [Bartley & Young, 2009] Ultrasound could conceivably be used in tandem with any one or more anti-biofilm agents.

Taurolidine is active against a wide range of microorganisms, including antibiotic-resistant bacteria, fungi, and mycobacteria.[Watson et al., 1995; Torres-Viera et al., 2000]  Taurolidine and its derivatives react with the bacterial cell wall, cell membrane, and endotoxins. Microbes are killed and the resulting toxins are inactivated, which reduces the inflammatory effect. Taurolidine is also used in the prevention and treatment of catheter related infections. [Zweich et al., 2013; Handrup et al., 2012; Chu et al., 2012; Diamanti et al., 2014] Taurolidine decreases bacterial adherence to host cells by destroying fimbriae (appendages used to stick to surfaces), which prevents biofilm formation. Bacterial resistance against taurolidine has yet to be observed. No systemic side effects have been identified. However, high concentrations (up to 5 mg/mL) are required for activity.

Derivatives of 2-aminoimidazoles have recently been developed as molecules that both inhibit biofilm formation and disperse bacterial biofilms [Richards & Melander, 2009]. Examples of natural products in this class include oroidin, ageliferin, and mauritiamine. [Mourabit & Potier, 2001; Huigens et al., 2007, 2008] These naturally occurring secondary metabolites are produced by marine plants and animals (e.g., sponges, coral) to keep them slime free [Kelly et al., 2003; Tsukamoto et al., 1996; Yamada, 1997]. 2-aminoimidazole/triazole conjugates (effective range, 50-150 µM) eliminate biofilm colonization, augment the action of conventional antibiotics, suppress multidrug resistance, and are not hemolytic at active concentrations. [Huigens et al., 2009] Unfortunately, the activity of these agents may be significantly impaired in vivo by calcium or manganese ions [Rogers et al., 2009; Rogers et al., 2010].

Baking Soda (sodium bicarbonate) is one of the most useful health tools around. It’s alkalizing effects notwithstanding, antibiofilm activity may be one of the important reasons for its wide ranging benefits.[Gawande, 2008] Bicarbonates also work well with bismuth thiols, which show optimum effects at alkaline pHs. [Domenico et al., 1997] Potassium bicarbonate may be the preferred oral form of baking soda, since potassium offsets the ill effects of a high-sodium diet, helps build bones, lowers blood pressure, etc. It also raises the pH of urine to significantly improve host defenses against biofilms in the urinary tract (see my blog on how to prevent urinary tract infections: https://thescienceofnutrition.me/2015/07/17/beat-urinary-tract-infections-with-nutrition/).

Mucus is also beneficial In the fight against bacteria. Polymers called mucins adhere to bacteria and prevent them from sticking together on a surface, making them harmless. [Caldara et al., 2012]  Mucin complexity makes the commercial production of synthetic mucin impractical. However, mucins from jellyfish may be a commercially viable source in the future. [Ohta et al., 2009]

All major religions promote fasting, and medical research is just beginning to appreciate the benefits of intermittent fasting, from normalizing hormone levels, improved mental clarity, to fighting infection. Fasting can starve microbes while improving immunity, and may help combat biofilms. [Janossy, 2015]

The overconsumption of sugar and refined, processed food has altered our gut biofilms in unhealthy ways, which predisposes us to disease. [http://www.nutraingredients.com/Research/Gut-microbiota-shifts-could-predict-diabetes-risk-suggests-study] Artificial sweeteners also alter the gut microflora in negative ways. [Suez et al., 2014] Sugar promotes the growth of pathogenic yeast and other fungal biofilms. [http://www.thecandidadiet.com/causes.htm]

On the other hand, sugar has been shown to boost the effectiveness of antibiotics against biofilms. Administering sugar with gentamicin cured mice with chronic urinary tract infections, and kept the bacteria from spreading to their kidneys. Perhaps by jump starting the germs’ metabolism with sugar, they can be coaxed out of the biofilm mode. [Allison et al., 2011]

Concluding Remarks

Antibiotic resistance is a crisis of historic proportions, and biofilms are a central part of that problem. Biofilm-related infections are inherently resistant to conventional antibiotic therapy, making them recurrent and chronic. Innovative therapeutic measures need to be developed to eradicate persistent infections. Effective treatments are still limited, and there’s much we don’t know about these new anti-biofilm agents. Many of the new agents are preferentially non-biocidal, so they won’t damage our friendly flora and work against us.

All told, the future appears bright for the anti-biofilm trade. Drug cocktails comprised of antibiotics and novel anti-biofilm agents will soon be developed to treat biofilm-associated infections. While this treatise is not an exhaustive analysis of all the possible anti-biofilm candidates under study, the anti-biofilm agents discussed may someday be part of the solution to some of medicine’s most urgent needs.

Follow Dr. Phil on Twitter: @drwillip


Abraham KP., Sreenivas J, Venkateswarulu TC, et al. Investigation of the potential antibiofilm activities of plant extracts. International Int J Pharm Pharm Sci 2012;4:282-5.

Al-Bakri AG, Othman G, Afifi FU. Determination of the antibiofilm, antiadhesive, and anti-MRSA activities of seven Salvia species. Pharmacogn Mag 2010;6:264-70.

Allison KR, Brynildsen MP, Collins JJ. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 2011;473:216–20.

Al Mourabit A, Potier P. Sponge’s molecular diversity through the ambivalent reactivity of 2-aminoimidazole: a universal chemical pathway to the oroidin-based pyrrole-imidazole alkaloids and their palau’amine congeners. Eur J Org Chem 2001:237-43.

Alves FRF, Neves MAS, Silva MG, et al. Antibiofilm and antibacterial activities of farnesol and xylitol as potential endodontic irrigants. Braz Dent J 2013;24:224-9 .

Bartley J, Young D. Ultrasound as a treatment for chronic rhinosinusitis. Med Hypotheses 2009;73:15–7.

Bodet C, Chandad F, Grenier D. Inhibition of host extracellular matrix destructive enzyme production and activity by a high molecular-weight cranberry fraction. J Periodontal Res 2007;42:159–68.

Bodet C, Chandad F, Grenier D. Anti-inflammatory activity of a high-molecular-weight cranberry fraction on macrophages stimulated by lipopolysaccharides from periodontopathogens. J Dent Res 2006;85:235-9.

Brickman AM, et.al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nature Neurosci 2014;17:1798-803.

Caldara M, Friedlander RS, Kavanaugh NL, et al. Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state. Current Biology 2012;22:2325–30.

Carmen JC, Roeder BL, Nelson JL, et al. Treatment of biofilm infections on implants with low-frequency ultrasound and antibiotics. Am J Infect Control 2005;33:78–82.

Carvalho I, Henriques M, Oliveira JC, Alves CFA, Piedade AP, Carvalho S. Influence of surface features on the adhesion of Staphyloccocus epidermidis to Ag–TiCN thin films. Sci Technol Adv Mat, 2013;14:035009

Chu H.-P, Brind J, Tomar R, Hill S. Significant reduction in central venous catheter-related bloodstream infections in children on HPN after starting treatment with Taurolidine Line Lock. JPGN 2012;55:403-7.

Darouiche RO, Mansouri MD, Gawande PV, Madhyastha S. Antimicrobial and antibiofilm efficacy of triclosan and DispersinB combination. J Antimicrob Chemother 2009;64:88–93.

DePas WH, Hufnagel DA, Lee JS, et al. Iron induces bimodal population development by Escherichia coli. PNAS 2012;110:2629–34.

Diamanti A., Capriati T., Iacono A. Recurrent catheter related bloodstream infections by Candida glabrata: Successful treatment with taurolidine. Clin Nutr 2014;33:367.

Domenico P, Baldassarri L, Schoch PE, Kaehler K, Sasatsu M, Cunha BA. Activities of bismuth thiols against staphylococci and staphylococcal biofilms. Antimicrob Agents Chemother 2001;45:1417-1421.

Domenico P, Tomas JM, Merino S, Rubires X, Cunha BA. Surface antigen exposure by bismuth-dimercaprol suppression of Klebsiella pneumoniae capsular polysaccharide. Infect Immun 1999;67:664-9.

Domenico P, Salo RJ, Novick SG, et al. Enhancement of bismuth antibacterial activity with lipophilic thiol chelators. Antimicrob Agents Chemother 1997;41:1697-703.

Domenico P, Reich J, Madonia W, Cunha BA. Resistance to bismuth among gram-negative bacteria is dependent upon iron and its uptake.  J Antimicrob Chemother  1996;38:1031-40.

Domenico P, Salo R, Straus DC, Hudson JC, Cunha BA. Salicylate or bismuth salts enhance opsonophagocytosis of Klebsiella pneumoniae. Infection 1992;20:66-72.

Domenico P, Landolphi DR, Cunha BA. Reduction of capsular polysaccharides and potentiation of aminoglycoside inhibition in gram-negative bacteria with bismuth subsalicylate. J Antimicrob Chemother 1991;28:801-10.

Domenico P, Hopkins T, Schoch PE, Cunha BA. Potentiation of aminoglycoside inhibition and reduction of capsular polysaccharide in Klebsiella pneumoniae with sodium salicylate. J Antimicrob Chemother 1990;25:903-14.

Dong Y, Chen S, Wang Z, Peng N, Yu J. Synergy of ultrasound microbubbles and vancomycin against Staphylococcus epidermidis biofilm. J Antimicrob Chemother 2013;68:816–26.

El-Feky MA, El-Rehewy MS, Hassan MA, et al. Effect of ciprofloxacin and N-acetylcysteine on bacterial adherence and biofilm formation on ureteral stent surfaces. Polish J Microbiol 2009;58:261-7.

Esser N, Paquot N, Scheen AJ. Anti-inflammatory agents to treat or prevent type 2 diabetes, metabolic syndrome and cardiovascular disease. Expert Opin Investig Drugs. 2015;24:283-307.

Farah A, Monteiro M, Donangelo CM, Lafay S. Chlorogenic acids from green coffee extract are highly bioavailable in humans. J Nutr 2008;138:2309-15.

Feldman M, Tanabe S, Howell A, Grenier D. Cranberry proanthocyanidins inhibit the adherence properties of Candida albicans and cytokine secretion by oral epithelial cells. BMC Comp Alt Med 2012;12:6

Finnegan S, Percival SL. EDTA: An antimicrobial and anti-biofilm agent for use in wound healing. Advances in Wound Care. 2014 doi:10.1089/wound.2014.0577.

Folsom JP, Baker B, Stewart PS. In vitro efficacy of bismuth thiols against biofilms formed by bacteria isolated from human chronic wounds. J Appl Microbiol 2011;111:989-96.

Frolkis VV, et al. Effect of enterosorption on animal lifespan. Biomater Artif Cells Artif Organs 1989;17:341-51.

Gawande PV, et al. Antibiofilm activity of sodium bicarbonate, sodium metaperiodate and SDS combination against dental unit waterline-associated bacteria and yeast. J Appl Microbiol 2008;105:986-92.

González-Ortiz G, Quarles Van Ufford H C, Halkes S Bart A, et al. New properties of wheat bran – anti-biofilm activity and interference with bacteria quorum-sensing systems. Envir Microbiol 2014;16:1346-53.

Gowrishankar S, Mosioma ND, Pandian SK. Coral-associated bacteria as a promising antibiofilm agent against methicillin-resistant and -susceptible Staphylococcus aureus biofilms. Evidence-Based Complementary and Alternative Medicine 2012, Article ID 862374, 16 pages

Hall-Stoodley L, Costerton JW, Stoodley P. Bacterial biofilms: from the natural environment to infectious diseases. Nat Rev Microbiol 2004;2:95-108.

Handrup M. M., Fuursted K., Funch P., Moeller J. K., Schroeder H. Biofilm formation in long term central venous catheters in children with cancer: a randomized controlled open-labelled trial of taurolidine versus heparin. APMIS 2012;120:794-801

He N, Hu J, Liu H et al. Enhancement of vancomycin activity against biofilms by using ultrasound-targeted microbubble destruction. Antimicrob Agents Chemother 2011;55:5331–7.

Huang CY, Chen YW, Kao TH, et al. Hyperbaric oxygen therapy as an effective adjunctive treatment for chronic Lyme disease. J Chin Med Assoc 2014;77:269-71.

Huang CB, Alimova Y, Myers TM, Ebersole JL. Short- and medium-chain fatty acids exhibit antimicrobial activity for oral microorganisms. Arch Oral Biol 2011;56:650-4.

Huigens RW, Rogers SA, Steinhauer AT, Melander C. Inhibition of Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa biofilm formation with a class of TAGE-triazole conjugates. Org Biomol Chem 2009;7:794-802.

Huigens RW, Ma L, Gambino C, et al. Control of bacterial biofilms with marine alkaloid derivatives. Mol Biosyst 2008;4:614-21.

Huigens RW, Richards JJ, Parise G, et al. Inhibition of Pseudomonas aeruginosa biofilm formation with bromoageliferin analogues. J Am Chem Soc 2007;129:6966-7.

Jakobsen TH, van Gennip M, Phipps RK. Ajoene, a sulfur-rich molecule from garlic, inhibits genes controlled by quorum sensing. Antimicrob Agents Chemother 2012;56:2314.

Janossy T. Biofilm in Lyme, Autism, Alzheimer’s and Dementia. 2015. http://oradix.com/pages/Anti%252dBiofilm%252dStrategies.html

Kalpana BJ, Aarthy S, Pandian SK. Antibiofilm activity of α-amylase from Bacillus subtilis S8-18 against biofilm forming human bacterial pathogens. Appl Biochem Biotechnol 2012;167:1778-94.

Karunanidhi A, Thomas R, van Belkum A, Neela V. In vitro antibacterial and antibiofilm activities of chlorogenic acid against clinical isolates of Stenotrophomonas maltophilia including the trimethoprim/sulfamethoxazole resistant strain. Biomed Res Int. 2013;2013:392058

Karwacki MT, Kadouri DE, Bendaoud M, et al. Antibiofilm activity of Actinobacillus pleuropneumoniae serotype 5 capsular polysaccharide. PLoS ONE 2013;8(5):e63844.

Kelly SR, Jensen PR, Henkel TP, et al. Effects of Caribbean sponge extracts on bacterial attachment. Aquat Microb Ecol 2003;31:175-82.

La VD, Howell AB, Grenier D. Anti-Porphyromonas gingivalis and anti-inflammatory activities of A-type cranberry proanthocyanidins. Antimicrob Agents Chemother 2010;54:1778–84.

Labrecque J, Bodet C, Chandad F, Grenier D. Effects of a high-molecular-weight cranberry fraction on growth, biofilm formation and adherence of Porphyromonas gingivalis. J Antimicrob Chemother 2006;58:439–43.

Lee JH, et.al. Apple flavonoid phloretin inhibits Escherichia coli O157:H7 biofilm formation and ameliorates colon inflammation in rats. Infect Immun 2011;79:4819-27.

Marambio-Jones C, Hoek EMV. A review of the antibacterial effects of silver nanomaterials and potential implications for human health and the environment. J Nanopart Res 2010;12:1531–51.

McLain N, Ascanio R, Baker C, Strohaver RA, Dolan JW. Undecylenic acid inhibits morphogenesis of Candida albicans. Antimicrob Agents Chemother  2000;44:2873-5.

McDonald AB. Dementia Caused by Borellia infection of the Central Nervous System. http://alzheimerborreliosis.net/wp-content/uploads/2012/10/Final_version_Philadelphia_Presentation.pdf

Morgan B. Microbial gangs are organised killers. https://cosmosmagazine.com/life-sciences/microbial-gangs-are-organised-killers. Cosmos, 4 May 2015.

Muller E, Al-Attar J, Wolff AG, Farber BF. Mechanism of salicylate-mediated inhibition of biofilm in Staphylococcus epidermidis, J Infect Dis 1998;177:501-3.

Nithya C, Devi MG, Karutha Pandian S. A novel compound from the marine bacterium Bacillus pumilus S6-15 inhibits biofilm formation in Gram-positive and Gram-negative species. Biofouling 2011;27:519–28.

O’Connor DJ, et. al. Resveratrol Inhibits Periodontal Pathogens In Vitro. Phytotherapy Research, 2011;25 http://onlinelibrary.wiley.com/doi/10.1002/ptr.3501/abstract?

Ogawa A, Furukawa S, Fujita S, et al. Inhibition of Streptococcus mutans biofilm formation by Streptococcus salivarius FruA. Appl Environ Microbiol. 2011;77:1572-80.

Ohta N, Sato M, Ushida K, et al. Jellyfish mucin may have potential disease-modifying effects. BMC Biotechnol 2009;9:98.

Penn-Barwell JG, Baker B, Wenke JC.Local bismuth thiols potentiate antibiotics and reduce infection in a contaminated open fracture model.J Orthop Trauma 2015;29:e73-8.

Pézer-Giraldo C, Rodriguez-Benito A, Maron FJ, et al. Influence of N-acetylcysteine on the formation of biofilm by S. epidermidis. J Antimicrob Chemother 1997;39:643-6.

Plate L, Marletta MA. Nitric oxide modulates bacterial biofilm formation through a multi-component cyclic-di-GMP signaling network. Mol Cell 2012;46:449–60.

Pollan M. Some of My Best Friends Are Germs. New York Times Magazine. May 15, 2013.

Partiwi SU, Lagendijk EL, Hertiani T. Antimicrobial effects of Indonesian medicinal plants extracts on planktonic and biofilm growth of Pseudomonas aeruginosa and Staphylococcus aureus. Intl J Pharm Pharmaceut Sci 2015;7:183-91.

Raja AF, Ali F, Khan IA, et al. Antistaphylococcal and biofilm inhibitory activities of acetyl-11-keto-β-boswellic acid from Boswellia serrata. BMC Microbiology 2011;11:54.

Rendueles O, Kaplan JB, Ghigo JM. Antibiofilm polysaccharides. Env Microbial 2013;15:334-46.

Richards, JJ, Melander C. Controlling bacterial biofilms. Chembiochem 2009;10:2287-94.

Rogers SA, Huigens RW III, Cavanagh J, Melander. C. Synergistic effects between conventional antibiotics and 2-aminoimidazole-derived antibiofilm agents. Antimicrob Agents Chemother. 2010;54:2112–8.

Rogers, S. A., R. W. Huigens, and C. Melander. A 2-aminobenzimidazole that inhibits and disperses Gram-positive biofilms through a zinc-dependent mechanism. J Am Chem Soc 2009;131:9868-9.

Rose J. Biofilms: The Good and the Bad. http://www.waterandhealth.org/biofilms-good-bad/ Dec, 2011.

Schachter B. Slimy business—the biotechnology of biofilms. Nature Biotechnol 2003;21:361-5.

Shan B, Cai Y, Brooks JD, Corke H. The in vitro antibacterial activity of dietary spice and medicinal herb extracts. Int J Food Microbiol 2007;117:112–9.

Steinberg D, Feldman M, Ofek I, Weiss EI. Effect of a high-molecular-weight component of cranberry on constituents of dental biofilm. J Antimicrob Chemother 2004;54:86–9.

Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 2014;514(7521):181-6.

Sun F,  Qu F, Ling Y, et al. Biofilm-associated infections, antibiotic resistance and novel therapeutic strategies. Future Microbiol  2013;8:877-86.

Tetz GV, Artemenko NK, Tetz VV. Effect of DNase and antibiotics on biofilm characteristics. Antimicrob Agents Chemother 2009;53:1204-09.

Torres-Viera, C.; Thauvin-Eliopoulos, C.; Souli, M.; et al.  Activities of taurolidine In vitro and in experimental enterococcal endocarditis. Antimicrob Agents Chemother 2000;44:1720–4.

Tsukamoto, S., H. Kato, H. Hirota, and N. Fusetani. Mauritiamine, a new antifouling oroidin dimer from the marine sponge Agelas mauritiana. J Nat Prod 1996;59:501-3.

Vikram A, et.al. Suppression of bacterial cell–cell signalling, biofilm formation and type III secretion system by citrus flavonoids, J Microbiol 2010;109:515–27.

Watson RW, Redmond HP, Mc Carthy J, et al. Taurolidine, an antilipopoly-saccharide agent, has immunoregulatory properties that are mediated by the amino acid taurine. J Leukoc Biol 1995;58:299–306.

Weiss EI, Kozlovsky A, Steinberg D, et al. A high molecular mass cranberry constituent reduces mutans streptococci level in saliva and inhibits in vitro adhesion to hydroxyapatite. FEMS Microbiol Lett 2004;232:89–92.

Weiss EI, Lev-Dor R, Kashamn Y et al. Inhibiting interspecies coaggregation of plaque bacteria with a cranberry juice constituent. J Am Dent Assoc 1998;129:1719–23.

Wu, H., Z. Song, M. Hentzer, J. B. Andersen, S. Molin, M. Givskov, and N. Hoiby. Synthetic furanones inhibit quorum-sensing and enhance bacterial clearance in Pseudomonas aeruginosa lung infection in mice. J Antimicrob Chemother 2004;53:1054-61.

Yamada AH, Kitamura K, Yamaguchi S, et al. Development of chemical substances regulating biofilm formation. Bull Chem Soc Jpn 1997;70:3061-9.

Yamanaka A, Kimizuka R, Kato T, Okuda K. Inhibitory effects of cranberry juice on attachment of oral streptococci and biofilm formation. Oral Microbiol Immunol 2004;19:150–4.

Zwiech R, Adelt M, Chrul S. A taurolidine-citrate-heparin lock solution effectively eradicates pathogens from the catheter biofilm in hemodialysis patients. Amer J Therap 2013.


39 thoughts on “Natural Anti-Biofilm Agents

  1. Pingback: Lyme Disease Resources | Still A Southern Gal

  2. I would like to combine some of the above agents to help prevent recurring urinary tract infections. My question is about dosage. I have lactoferrin, NAC, Pepto, Potassium Bicarbonate and a cranberry product with 36 mg of PAC. Are these effective at normal doses or do they need to be increased to be effective as biofilm disruptors. Also, do these agents only effect pathenogenic films? Finally, the research on sugar indicated eating some may help draw out the pathenogenic bacteria where they can be more easily killed by the agents, so add a cookie or a sweet treat to the cocktail?

    • My article stressed getting your urine pH up to near 7, and eating as many foods and supplements you can containing PAC, like cranberries, green tea, chocolate, coffee, red wine, etc. If you take an eighth of a tsp of potassium bicarbonate twice daily, that should do the trick. Take it on an empty stomach so as not to disturb digestion. Your pee will take on a stronger odor, but that’s part of prevention. You might consider backing off the bicarb to one eighth tsp per day after a month or so, but keeping monitoring your urine pH levels.

  3. Pingback: Anonymous

  4. Most of my fellow Lyme sufferers believe bismuth will harm them. I do not know why but that is what I used to get my gut healed. I am happy you posted this. You definately have done a lot of research. Thank you.

    • Bismuth is a heavy metal, but don’t let that fool you. It has little toxicity, which shows up only after long-term, heavy usage. That’s why my bismuth thiols are superior to Pepto-Bismol, since 100-fold less bismuth is needed, and they have the potential to completely rid biofilms. They are currently in Phase 2 clinical trials for wound infections, and are not available yet for personal use. Thanks for the re-blog!

  5. If bio films can maintain both pathenogenic and healthy bacterial communities, won’t the good get wiped out with the bad? Thanks.

    • Yes, the good guys also make biofilms. You don’t want to start killing everything, because you kill the good guys, too. But you might want to diminish the biofilm overgrowth to reduce toxicity and help the immune system mop up the bad guys. Sometimes those bad guys were once good guys that turned on you because of poor health or lack of nutrition. It’s not black and white.

      • Thanks for mentioning the bacterial switching. My reason for entering medical school was to study the L-form bacteria and their neomorphogenic tendencies. I was interested in showing that cell wall deficient bacteria can change to suit their environment, and the possibility of shifting CWD bacteria causing us harm, to beneficial allies, after the original ideas put forth by Bechamps. My idea was bigger than the research facility at my school, unfortunately–CWD bacteria are notoriously difficult to grow. And biofilms were barely being studied when I started!

      • I once wanted to go to med school, but would never have discovered my anti-biofilm agents (bismuth thiols) if I had. Plus, I have no bedside manner, so I belong in the lab. I had a fleeting interest in L-form bacteria, but also did not have the facilities to study them. Life happens when you’re busy making other plans, so they say.

  6. Thank you Dr. Willip. My 93 year old Mother has recurring UTIs and the antibiotics keep getting stronger, now taken via IV. They make her so very sick. It’s no way to live. I have her taking D Mannose which seems to work in a similar way to suggestions here, but only for eColi so maybe that is why she still gets some UTI?. Should I try adding Potassium Bicarbonate in addition to the D Mannose, or instead of? And what dose of Bismuth Phiols with the Bicarbonate? Lastly, what do you suggest for flavor? Can she add it to cranberry juice, or any juice? THANK YOU!

    • Nancy: I’ve seen excellent reviews for D-Mannose on Amazon . . . it “baits” bacteria to let go of the urethra and bind to its own molecules so they can be flushed out. If it doesn’t work, I’d ask your mother’s physician if the infection could possibly be viral (herpes/chicken pox complex is extremely common) or fungal (yeasts are also incredibly common). I’ve heard accounts of people who applied organic virgin coconut oil externally at the opening of the urethra and had success, as the oil had to some extent “wicked” up the urethra. Coconut oil is active against bacteria, viruses and fungi.

    • Nancy: I’ve seen excellent reviews for D-Mannose on Amazon . . . it “baits” bacteria (don’t think it’s only one species) to let go of the urethra and bind to its own molecules so they can be flushed out. If it doesn’t work, I’d ask your mother’s physician if the infection could possibly be viral (herpes/chicken pox complex is extremely common) or fungal (yeasts are also incredibly common). I’ve heard accounts of people who applied organic virgin coconut oil externally at the opening of the urethra and had success, as the oil had to some extent “wicked” up the urethra (reapplying often). Coconut oil is said to be active against bacteria, viruses and fungi.

  7. How do you kill the biofilms from e coli when it involves bacterial vaginosis? What kind of enzyme/acid would kill e coli? How do you do it in such a way that it will kill off the bad pathogens but help the good bacteria? How do you help the immune system mop up the bad guys?

    • you might have to treat with an anti-biofilm cocktail, and then replenish with probiotic strains. consider getting vaginal secretions from a healthy donor.

      • Is their something that can be used to kill biofilms in a skin yeast infection (in the armpits) that was caused by antibacterial soap? Something that will spare the good flora and return things to the right balance?

      • There are some skin probiotics available. Stop using antibacterial soap for sure. You might look into natural anti fungal oils like tea tree, clove, thyme and oregano oils. I use small amounts of baking soda as a deodorant. It works like a charm, and may also keep the fungus in check.

    • Jane: for topical yeast infections (which cause everything from dandruff, to itchy rashes in feet, groin, armpits, skin folds etc, to random skin peeling, and even possibly eczema): We discovered Derman Ointment (hard to find but I just grabbed the last one at Target). It works for my family. Contains zinc undecylenate and undecylenic acid (a fatty acid made from castor oil), which Dr. Phil mentions in this article! Great stuff and not harmful like the powerful “azole” drugs that are toxic to the liver. Apple cider vinegar seems to work, but it’s very caustic and makes the rash burn; Derman kills it “softly”. A healthy skin barrier is acidic, and yeast hates an acidic environment! Yeast thrives on oils with carbon chains between 11-24 carbons (which most lotions have: mineral oil, cocoa butter, shea butter, stearic acid, olive oil/oleic acid). Look for lotions and soaps w/fatty acids containing 10 or fewer carbon chains–essential oils or the MCT oils–or very long carbon chains (jojoba oil has 26). Also great are lactic acid, alpha hydroxy acids, urea, and salycilic acid (crushed aspirin can supply this). These all make an environment hostile to yeast yet great for skin. I just discovered that Trader Joe’s brand personal care items contain many of these ingredients (no, I don’t represent them or Derman’s)! 🙂 Good luck!

    • Jane: topical yeast (from dandruff and flaking, to itchy red rashes of all kinds) is killed effectively by the undecylenic acid (mentioned by Dr.Willip above) and zinc undecylenate contained in Derman Ointment! Hard to find but excellent, and not toxic like the “azole’ drugs and ointments. Lotions and soaps with essential oils, MCT oils, jojoba oil, lactic acid, urea, salicylic acid and alpha-hydroxy acids make an environment that’s hostile to yeast while healthy for skin. Good luck!

    • Better to go natural than with antibiotics. You might try a couple of modalities I mentioned to look for synergy. Some people swear by colloidal silver. Dr. Mercola talked about it today online. It will be a year or more before my bismuth thiol drug is approved for similar purposes. I would also consider extra vitamin D (5000 IU), fish oil, mixed carotenoids, and natural vitamin E complex.

  8. Thanks so much for this. Very informative and detailed. Using it to try and fix an intestinal overgrowth of an unknown kind. Are there any particularities about the ultrasound? Wavelengths or something? Thanks again.

  9. hi, i have interstitial cystitis for 1 1/2 years now. am i too late to do a biofilm busting protocol for candida? i read up and down this page but am overwhelmed with info. what do you recommend i take for bladder/intestinal biofilm? what antibiotics will work best in conjunction?

    • Victoria,
      I am not a licensed health practitioner. You should be working with a naturopath, or share my blog post with an integrative physician open to experimenting. My bismuth thiols (BTs) will not be ready to treat cystitis for many years. Beyond anti-biofilm agents, you should also consider natural antimicrobials in that discussion, as well as anti-inflammatory agents. You can quell inflammation with natural substances, like turmeric, ginger, aloe, chamomile, celery, garlic, fish oil, vitamin D3, etc. Keeping experimenting, and improving your diet.

  10. Pingback: Anti-biofilm Strategies How To Eradicate Candida Biofilms | Check Howto

  11. Pingback: Natural Anti-Biofilm Agents – Lee's Stuff

  12. Pingback: Biofilm: A Secret Weapon in the Arsenal? - Return2Health

  13. Thanks for the article. BTs might be effective on the Endodontic infections which mainly caused by E. Faecalis and C. Albicans. Ex vivo or in vivo studies are needed.

    • Certain BTs do work well against E. faecalis and C. albicans. It’s worth employing them selectively in the mouth, especially against bad biofilms. We haven’t gotten that far yet, however. Our small company is focused on serious medical biofilms at present.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s