# Natamycin

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"E235" redirects here. For the Japanese train type, see [E235 series](/source/E235_series).

**Natamycin**, also known as **pimaricin**, is an [antifungal medication](/source/Antifungal_medication) used to treat [fungal infections](/source/Fungal_infections) around the eye.[1][2] This includes infections of the [eyelids](/source/Blepharitis), [conjunctiva](/source/Conjunctivitis), and [cornea](/source/Keratitis).[1] It is used as [eyedrops](/source/Eyedrops).[1] Natamycin is also used in the food industry as a [preservative](/source/Preservative).[2]

[Allergic reactions](/source/Allergic_reactions) may occur.[1] It is unclear if medical use during [pregnancy](/source/Pregnancy) or [breastfeeding](/source/Breastfeeding) is safe.[1] It is in the [macrolide](/source/Macrolide) and [polyene](/source/Polyene_antimycotic) families of medications.[1] It results in [fungal death](/source/Fungicidal) by altering the [cell membrane](/source/Cell_membrane).[1]

Natamycin was discovered in 1955 and approved for medical use in the United States in 1978.[1][2] It is on the [World Health Organization's List of Essential Medicines](/source/WHO_Model_List_of_Essential_Medicines).[3] It is produced by [fermentation](/source/Fermentation) of certain types of the bacterium *[Streptomyces](/source/Streptomyces)*.[1][4]

## Uses

### Medical

Natamycin is used to treat fungal infections, including *[Candida](/source/Candida_(genus))*, *[Aspergillus](/source/Aspergillus)*, *[Cephalosporium](/source/Cephalosporium)*, *[Fusarium](/source/Fusarium)*, and *[Penicillium](/source/Penicillium)*. It is applied topically as a cream, in eye drops, or (for oral infections) in a [lozenge](/source/Throat_lozenge). Natamycin shows negligible absorption into the body when administered in these ways. When taken orally, little or none is absorbed from the gastrointestinal tract, making it inappropriate for systemic infections.[5] Natamycin lozenges are used by veterinarians for [oral thrush](/source/Oral_thrush).[6]

### Food

Natamycin has been used for decades in the food industry as a hurdle to fungal outgrowth in dairy products and other foods. Potential advantages for the usage of natamycin might include the replacement of traditional chemical preservatives, a neutral flavor impact, and less dependence on [pH](/source/PH) for efficacy, as is common with chemical preservatives. It can be applied in a variety of ways: as an aqueous suspension (such as mixed into a [brine](/source/Brine)) sprayed on the product or into which the product is dipped, or in powdered form (along with an [anticaking agent](/source/Anticaking_agent) such as [cellulose](/source/Cellulose)) sprinkled on or mixed into the product.[citation needed]

Natamycin is approved for various dairy applications in the United States. More specifically, natamycin is commonly used in products such as cream cheeses, cottage cheese, sour cream, yogurt, shredded cheeses, cheese slices, and packaged salad mixes. One of the reasons for food producers to use natamycin is to replace the artificial preservative [sorbic acid](/source/Sorbic_acid).[7] Natamycin is also known to diffuse slower and lesser into cheese when compared to sorbate, which could otherwise cause undesirable changes to the flavor.[8]

As a [food additive](/source/Food_additive), it has [E number](/source/E_number) E235. Throughout the European Union, it is approved only as a surface preservative for certain cheese and dried sausage products. It must not be detectable 5 mm below the rind. While natamycin is approved in different applications at different levels in the world, it is approved in over 150 countries worldwide.[9]

While not currently approved for use on meats in the United States, some countries allow natamycin to be applied to the surface of dry and fermented sausages to prevent mold growth on the casing. Sausages that contain cheese, even in countries that do not allow its use on meats, may contain and list natamycin as an ingredient.

The [European Food Safety Authority](/source/European_Food_Safety_Authority) (EFSA) panel took over the responsibilities of providing scientific food safety advice to the EU from the [Scientific Committee on Food](/source/Scientific_Committee_on_Food) in 2002.[10] In 2009, the EFSA considered the proposed use levels of natamycin are safe if it is used for the surface treatment for these cheese and sausage types.[11]

## Safety

Natamycin does not have [acute toxicity](/source/Acute_toxicity). In animal studies, the lowest found was 2.5–4.5 g/kg.[12] In rats, the LD50 is ≥2300 mg/kg, and doses of 500 mg/kg/day over two years caused no detectable differences in survival rate, growth, or incidence of [tumors](/source/Tumors). The [metabolites](/source/Metabolites) of natamycin also lack toxicity. The breakdown products of natamycin under various storage conditions may have a lower LD50 than natamycin, but in all cases, the numbers are quite high. In humans, a dose of 500 mg/kg/day repeated over multiple days caused nausea, vomiting, and diarrhea.[13]

No evidence shows natamycin, at either pharmacological levels or levels encountered as a food additive, can harm normal [intestinal flora](/source/Intestinal_flora), but definitive research may not be available.[13] However, some people are allergic to natamycin.[14]

The EFSA has concluded that the use of natamycin as a food additive has no relevant risk for the development of [resistant](/source/Antibiotic_resistance) fungi.[11]

## Mechanism of action

Natamycin inhibits the growth of fungi by specifically binding to [ergosterol](/source/Ergosterol) present in fungal cell membranes. Natamycin inhibits amino acid and glucose transport proteins leading to a loss of nutrient transport across the plasma membrane. While this binding is reversible, ergosterol binding acts as a universal mechanism of fungal inhibition, allowing natamycin to act on diverse fungal pathogens from *[Saccharomyces](/source/Saccharomyces)* yeast to *[Aspergillus](/source/Aspergillus)* moulds. Natamycin is unique amongst related antifungals specifically because it does not directly cause membrane permeabilization.[15][16][17] Structurally-related antibiotics with similar binding properties are thought to produce hydrophilic channels that allow leakage of potassium and sodium ions from the cell.[18]

Natamycin has very low solubility in water; however, natamycin is effective at very low levels. Its [minimum inhibitory concentration](/source/Minimum_inhibitory_concentration) is less than 10 [ppm](/source/Parts_per_million) for most molds.[citation needed]

## Biochemistry

Natamycin is produced as a [secondary metabolite](/source/Secondary_metabolite) by some *Streptomyces* species: *[S. natalensis](/source/Streptomyces_natalensis)*, *[S. lydicus](/source/Streptomyces_lydicus)*, *[S. chattanoogensis](/source/Streptomyces_chattanoogensis)* and *[S. gilvosporeus](/source/Streptomyces_gilvosporeus)*.[4] Structurally, its core is a [macrolide](/source/Macrolide) containing a [polyene](/source/Polyene) segment, with [carboxylic acid](/source/Carboxylic_acid) and [mycosamine](/source/Mycosamine) groups attached. As with other [polyene antimycotics](/source/Polyene_antimycotic), the [biosynthesis](/source/Biosynthesis) begins with a series of [polyketide synthase](/source/Polyketide_synthase) modules, followed by additional enzymatic processes for oxidation and attachment of the substituents.[19]

Natamycin is produced on an industrial scale by fermentation of various *Streptomyces* strains, including *S. chattanoogensis* L10.[19]

## History

Natamycin was first isolated in 1955 from fermentation broth of a *Streptomyces natalensis* cell culture.[20] It was originally named *pimaricin* to honor [Pietermaritzburg](/source/Pietermaritzburg), where *Streptomyces natalensis* was acquired. Pimaricin was later renamed after the [World Health Organization](/source/World_Health_Organization) (WHO) mandated that antibiotics produced by *Streptomyces* end in –mycin. The name *natamycin* was chosen in reference to the *natalensis* species name.[20]

## Society and culture

Natamycin appears on [Whole Foods](/source/Whole_Foods_Market)' "Unacceptable Ingredients for Food" list.[21]

## References

1. ["Natamycin"](https://www.drugs.com/monograph/natamycin.html). The American Society of Health-System Pharmacists. Retrieved 8 December 2017.

1. Davidson PM, Juneja VK, Branen J (2001). ["Antimicrobial Agents"](https://books.google.com/books?id=87XK5Uwvs94C&pg=PA599). *Food Additives*. CRC Press. pp. 599–600. ISBN 978-0-8247-4170-9.

1. *World Health Organization model list of essential medicines: 21st list 2019*. Geneva: [World Health Organization](/source/World_Health_Organization). 2019. [hdl:10665/325771](https://hdl.handle.net/10665/325771). WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.

1. Aparicio JF, Barreales EG, Payero TD, Vicente CM, de Pedro A, Santos-Aberturas J (January 2016). "Biotechnological production and application of the antibiotic pimaricin: biosynthesis and its regulation". *Applied Microbiology and Biotechnology*. **100** (1): 61–78. [doi:10.1007/s00253-015-7077-0](https://doi.org/10.1007/s00253-015-7077-0). [PMC 4700089](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700089). [PMID 26512010](https://pubmed.ncbi.nlm.nih.gov/26512010)

1. Brayfield A (2014). *Martindale: The Complete Drug Reference*. 38th ed. London: Pharmaceutical press. ISBN 978-0-85711-139-5.

1. ["Topical Antifungal Drugs: Natamycin"](http://cpharm.vetmed.vt.edu/VM8784/antimicrobials/Classes/antifungals.cfm). Virginia-Maryland Regional College of Veterinary Medicine. [Archived](https://web.archive.org/web/20170407021124/http://cpharm.vetmed.vt.edu/VM8784/antimicrobials/Classes/antifungals.cfm) 7 April 2017 at the Wayback Machine.)

1. ["Kraft Singles Ditch Artificial Preservatives"](https://www.nbcnews.com/business/consumer/kraft-singles-ditch-artificial-preservatives-n27446). *[NBC News](/source/NBC_News)*. 11 February 2014. [Archived](https://web.archive.org/web/20221008215656/https://www.nbcnews.com/business/consumer/kraft-singles-ditch-artificial-preservatives-n27446) 8 October 2022 at the Wayback Machine.

1. Youssef AM, Assem FM, El-Sayed SM, Salama H, Abd El-Salam MH (2017). "Utilization of Edible Films and Coatings as Packaging Materials for Preservation of Cheeses". *Journal of Packaging Technology and Research*. **1** (2): 87–99. [doi:10.1007/s41783-017-0012-3](https://doi.org/10.1007/s41783-017-0012-3). [S2CID 257086547](https://api.semanticscholar.org/CorpusID:257086547)

1. ["Regulatory and Approval Information"](https://www.natamycin.com/regulatory). *Natamycin.com*

1. ["Safety and regulation: the formal process for analyzing the test data on food additives"](http://www.understandingfoodadditives.org/pages/Ch3p1.htm). *understandingfoodadditives.org*. [Archived](https://web.archive.org/web/20140107002148/http://www.understandingfoodadditives.org/pages/Ch3p1.htm) 7 January 2014 at the Wayback Machine.

1. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) (December 2009). ["Scientific Opinion on the use of natamycin (E 235) as a food additive."](http://www.efsa.europa.eu/en/efsajournal/pub/1412). *EFSA Journal*. **7** (12): 1412. [doi:10.2903/j.efsa.2009.1412](https://doi.org/10.2903/j.efsa.2009.1412)

1. Oostendorp JG (1981). "Natamysin(R)". *Antonie van Leeuwenhoek*. **47** (2): 170–171. [doi:10.1007/bf02342201](https://doi.org/10.1007/bf02342201). [S2CID 264007289](https://api.semanticscholar.org/CorpusID:264007289)

1. Mattia A, Dr Cerniglia C, Baines J. ["Safety evaluation of certain food additives and contaminants: natamicin (pimaricin)."](http://www.inchem.org/documents/jecfa/jecmono/v48je06.htm). *WHO Food Additives Series #48*. International Programme on Chemical Safety (IPCS)

1. ["Natamycin"](http://www.rxlist.com/natacyn-side-effects-drug-center.htm). *RxList*

1. te Welscher YM, ten Napel HH, Balagué MM, Souza CM, Riezman H, de Kruijff B, Breukink E (March 2008). "Natamycin blocks fungal growth by binding specifically to ergosterol without permeabilizing the membrane". *The Journal of Biological Chemistry*. **283** (10): 6393–6401. [doi:10.1074/jbc.M707821200](https://doi.org/10.1074/jbc.M707821200). [PMID 18165687](https://pubmed.ncbi.nlm.nih.gov/18165687)

1. Van Leeuwen MR, Golovina EA, Dijksterhuis J (June 2009). "The polyene antimycotics nystatin and filipin disrupt the plasma membrane, whereas natamycin inhibits endocytosis in germinating conidia of Penicillium discolor". *Journal of Applied Microbiology*. **106** (6): 1908–1918. [doi:10.1111/j.1365-2672.2009.04165.x](https://doi.org/10.1111/j.1365-2672.2009.04165.x). [PMID 19228256](https://pubmed.ncbi.nlm.nih.gov/19228256). [S2CID 2873514](https://api.semanticscholar.org/CorpusID:2873514)

1. te Welscher YM, van Leeuwen MR, de Kruijff B, Dijksterhuis J, Breukink E (July 2012). "Polyene antibiotic that inhibits membrane transport proteins". *Proceedings of the National Academy of Sciences of the United States of America*. **109** (28): 11156–11159. [Bibcode:2012PNAS..10911156T](https://ui.adsabs.harvard.edu/abs/2012PNAS..10911156T). [doi:10.1073/pnas.1203375109](https://doi.org/10.1073/pnas.1203375109). [PMC 3396478](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3396478). [PMID 22733749](https://pubmed.ncbi.nlm.nih.gov/22733749)

1. Nedal A, Sletta H, Brautaset T, Borgos SE, Sekurova ON, Ellingsen TE, Zotchev SB (November 2007). "Analysis of the mycosamine biosynthesis and attachment genes in the nystatin biosynthetic gene cluster of Streptomyces noursei ATCC 11455". *Applied and Environmental Microbiology*. **73** (22): 7400–7407. [Bibcode:2007ApEnM..73.7400N](https://ui.adsabs.harvard.edu/abs/2007ApEnM..73.7400N). [doi:10.1128/AEM.01122-07](https://doi.org/10.1128/AEM.01122-07). [PMC 2168226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2168226). [PMID 17905880](https://pubmed.ncbi.nlm.nih.gov/17905880)

1. Liu SP, Yuan PH, Wang YY, Liu XF, Zhou ZX, Bu QT, Yu P, Jiang H, Li YQ (April 2015). "Generation of the natamycin analogs by gene engineering of natamycin biosynthetic genes in Streptomyces chattanoogensis L10". *Microbiological Research*. **173**: 25–33. [doi:10.1016/j.micres.2015.01.013](https://doi.org/10.1016/j.micres.2015.01.013). [PMID 25801968](https://pubmed.ncbi.nlm.nih.gov/25801968)

1. ["The origins of natamycin"](http://www.natamycinvgp.com/the-origins-of-natamycin/). [Archived](https://web.archive.org/web/20140716020303/http://www.natamycinvgp.com/the-origins-of-natamycin/) 16 July 2014 at the Wayback Machine. Natamycin was isolated for the first time in 1955 in the Gist-brocades research laboratories, from the fermentation broth of a culture of Streptomyces natalensis.

1. ["Unacceptable Ingredients for Food"](http://www.wholefoodsmarket.com/about-our-products/quality-standards/food-ingredient). *Whole Foods Market IP. L.P.*. [Archived](https://web.archive.org/web/20180102192408/http://www.wholefoodsmarket.com/about-our-products/quality-standards/food-ingredient) 2 January 2018 at the Wayback Machine.

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Adapted from the Wikipedia article [Natamycin](https://en.wikipedia.org/wiki/Natamycin) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Natamycin?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.