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| Clinical data | |
|---|---|
| Trade names | Natacyn, others |
| AHFS/Drugs.com | Monograph |
| Routes of administration | Eye drops[1] |
| ATC code | |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEMBL | |
| E number | E235(preservatives) |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.028.803 |
| Chemical and physical data | |
| Formula | C33H47NO13 |
| Molar mass | 665.733 g·mol−1 |
| 3D model (JSmol) | |
| Density | 1.35 g/ml g/cm3 |
| Melting point | Darkens at ±200 °C with vigorous decomposition at 280-300 °C |
| Solubility in water | 0.39 mg/ml |
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Natamycin, also known aspimaricin, is anantifungal medication used to treatfungal infections around the eye.[1][2] This includes infections of theeyelids,conjunctiva, andcornea.[1] It is used aseyedrops.[1] Natamycin is also used in the food industry as apreservative.[2]
Allergic reactions may occur.[1] It is unclear if medical use duringpregnancy orbreastfeeding is safe.[1] It is in themacrolide andpolyene families of medications.[1] It results infungal death by altering thecell membrane.[1]
Natamycin was discovered in 1955 and approved for medical use in the United States in 1978.[1][2] It is on theWorld Health Organization's List of Essential Medicines.[3] It is produced byfermentation of certain types of the bacteriumStreptomyces.[1][4]
Natamycin is used to treat fungal infections, includingCandida,Aspergillus,Cephalosporium,Fusarium, andPenicillium. It is applied topically as a cream, in eye drops, or (for oral infections) in alozenge. 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 fororal thrush.[6]
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 onpH 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 abrine) sprayed on the product or into which the product is dipped, or in powdered form (along with ananticaking agent such ascellulose) 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 preservativesorbic 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 afood additive, it hasE 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 don't allow its use on meats, may contain and list natamycin as an ingredient.
TheEuropean Food Safety Authority (EFSA) panel took over the responsibilities of providing scientific food safety advice to the EU from theScientific 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]
Natamycin does not haveacute toxicity. In animal studies, the lowestLD50 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 oftumors. Themetabolites 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 normalintestinal 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 ofresistant fungi.[11]
Natamycin inhibits the growth of fungi by specifically binding toergosterol 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 fromSaccharomyces yeast toAspergillus 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. Itsminimum inhibitory concentration is less than 10 ppm for most molds.[citation needed]
Natamycin is produced as asecondary metabolite by someStreptomyces species:S. natalensis,S. lydicus,S. chattanoogensis andS. gilvosporeus.[4] Structurally, its core is amacrolide containing apolyene segment, withcarboxylic acid andmycosamine groups attached. As with otherpolyene antimycotics, thebiosynthesis begins with a series ofpolyketide 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 variousStreptomyces strains, includingS. chattanoogensis L10.[19]
Natamycin was first isolated in 1955 from fermentation broth of aStreptomyces natalensis cell culture.[20] It was originally namedpimaricin to honorPietermaritzburg, whereStreptomyces natalensis was acquired. Pimaricin was later renamed after theWorld Health Organization (WHO) mandated that antibiotics produced byStreptomyces end in –mycin. The namenatamycin was chosen in reference to thenatalensis species name.[20]
Natamycin appears onWhole Foods' "Unacceptable Ingredients for Food" list.[21]
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.
