Manufacturing Process

The Fermentation Process: The process by which this antifungal substance is produced is an aerobic fermentation of an aqueous nutrient medium The Fermentation Process: The process by which this antifungal substance is produced is an aerobic fermentation of an aqueous nutrient medium.In more detail the nutrient medium used may contain sources of carbon such as starch, hydrolyzed starch, sugars such as lactose, maltose, dextrose, sucrose, or sugar sources such as molasses; alcohols, such as glycerol and mannitol; organic acids, such as citric acid and acetic acid; and various natural products which may contain other nutrient materials in addition to carbonaceous substances.Nitrogen sources include proteins, such as casein, zein, lactalbumin; protein hydrolyzates such proteoses, peptones, peptides, and commercially available materials, such as N-Z Amine which is understood to be a casein hydrolyzate; also corn steep liquor, soybean meal, gluten, cottonseed meal, fish meal, meat extracts, stick liquor, liver cake, yeast extracts and distillers' solubles; amino acids, urea, ammonium and nitrate salts. Such inorganic elements as sodium, potassium, calcium and magnesium; and chlorides, sulfates, phosphates and combinations of these anions and cations in the form of mineral salts may be advantageously used in the fermentation.The so-called trace elements, such as boron, cobalt, iron, copper, zinc, manganese, chromium, molybdenum and still others may also be used to advantage. Generally, these trace elements occur in sufficient quantities in the carbonaceous and nitrogenous constituents of the medium, particularly if derived from natural sources, or in the tap water, and the addition of further quantities of these trace elements may consequently be unnecessary.The fermentation liquor is aerated in the customary manner by forcing sterile air through the fermenting mixture usually at the rate of about 1 volume of air per volume of fermentation medium per minute. To minimize contamination with foreign microorganisms, the fermentation vessels should be closed and a pressure of 2 to 15 pounds above atmospheric pressure maintained in the vessel. In addition to the agitation provided by aeration, mechanical agitation is generally desirable. Antifoaming agents, such as 1% octadecanol in lard oil, may be added from time to time as required to prevent excessive foaming. Fermentation is conducted at a temperature preferably on the order of 26°C to 30°C but may be as low as 17°C or as high as 42°C.The time required for maximum production of the antifungal substance will vary considerably depending upon other conditions of the fermentation. Generally, about 48 hours is required before appreciable quantities of the antifungal substance are detected in the medium. The production of the antifungal substance increases with time, and the fermentation may run as long as 120 hours. The hydrogen ion conditions normally vary from about pH 6 to pH 8.0, although deviations from these values are permissible, according to British Patent 846,933. The reader is referred to the patents cited for detals of pimaricin purification.

Therapeutic Function

Antibacterial (ophthalmic)

Biological Functions

Natamycin, also known as pimaracin, belongs to the polyene family of antibiotics; (a group of antifungal agents which target and bind to eukaryotic sterols and specifically ergosterol), and it is a secondary metabolite of Streptomyces natalensis . Very low levels (10–20 ppm) are needed to inhibit almost all yeasts and molds, while no amount of natamycin is sufficient to inhibit most bacteria, as they lack the sterol targeted by natamycin (some gram-positive types may be susceptible). Thus, natamycin may be used to retard the growth of fungi in meat products to which fermentative cultures are added, and is typically applied as a surface treatment (i.e., dip or spray). Resistant organisms are not typically encountered even though natamycin has been used as a food preservative for more than three decades. Unlike most bacteriocins, natamycin is toxic to eukaryotes. Acceptable daily intake of natamycin for humans is 0–0.3 mg/kg of body weight.

Antimicrobial activity

The spectrum of Natamycin's activity is somewhat narrower than that of amphotericin and nystatin, but at the same time, it is less toxic. It exhibits especially pronounced activity against a few strains of Fusarium and Cefalosporium. Natamycin is a drug for treating superficial fungal infections, and it is used only for ophthalmologic purposes. Synonyms of this drug are pimafucin, pimaricin, tennecetin, and others.

Safety Profile

Poison by intravenous, intramuscular, subcutaneous, and intraperitoneal routes. Moderately toxic by ingestion. When heated to decomposition it emits toxic fumes of NOx. Used as an antibacterial agent.

Synthesis

Natamycin, a mixture of stereoisomeric 22-[(3-amino-3,6-dideoxy-β-Dmannopyranosyl)oxy]-1,3,26-trihydroxy-12-methyl-10-oxo-6,11,28-trioxatricyclo[22.3.1.0.5,7]-octacosa-8,14,16,18,20,penten-25-carboxylic acid (35.1.3), like amphotericin and nystatin, is a polyene antibiotic that is isolated from the products of the vital activity of the actinomycete Streptomyces natalensis.

Veterinary Drugs and Treatments

Natamycin is a semisynthetic polyene antibiotic. Natamycin is poorly water-soluble and will not penetrate the intact corneal epithelium. Natamycin is the only antifungal agent approved for use on the eye and the only commercially available eye drug for treatment of fungal keratitis.

Brand name

Natacyn (Alcon).

General Description

Natamycin (pimaricin; Natacyn) is a polyene antibiotic obtainedfrom cultures of Streptomyces natalensis.The natamycin structure consists of a 26-membered lactonering containing a tetraene chromophore, an α,β-unsaturatedlactone carbonyl group, three hydroxyl groups, a carboxyl group, a trans epoxide, and a glycosidically joined mycosamine.Like the other polyene antibiotics, natamycin isamphoteric.The smaller polyenes are fungistatic and fungicidal within thesame concentration range.Natamycin possesses in vitro activity against severalyeasts and filamentous fungi, including Candida,Aspergillus, Cephalosporium, Penicillium, and Fusariumspp. The drug is supplied as a 5% ophthalmic suspension intendedfor the treatment of fungal conjunctivitis, blepharitis,and keratitis.