Numbered antibiotics

Propanol-pyridine-acetic acid-water (IS 10 3 12), descending, 48h, 2S°C front runs off end of paper Detection 

Ninhydrin (0.2% in 93% ethanol). Gives characteristic yellow-blue color Kf 

I-Butanol satd. with water containing 2% p-tolu-enesulfonic acid Detection 

Water satd. n-butanol + 0.2% / -toluenesul-fonic acid 

n-Butanol satd. with aq. 0.2S M disodium hydrogen phosphate, pH 9.3 

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The majority of bacteria are Gram-negative organisms and the coli-aerogenes group account for only a small fraction. Bdellovibrio bacteri-ovorus which attacks bacteria reduces the bacterial numbers. Antibiotic-resistant aeromonads have been isolated from some samples. Nitrosomonas spp. are also present and are responsible for nitrification of ammonia. 

Since 1950 a number of polyether antibiotics have been discovered using fermentation technol ogy They are characterized by the presence of sev eral cyclic ether structural units as illustrated for the case of monensm in Figure 16 3a Monensin and other naturally occurring polyethers are similar to crown ethers in their ability to form stable complexes... 

Although a tremendous number of fermentation processes have been researched and developed to various extents, only a couple of hundred ate used commercially. Fermentation industries have continued to expand in terms of the number of new products on the market, the total volume (capacity), and the total sales value of the products. The early 1990s U.S. market for fermentation products was estimated to be in the 9-10 x 10 range. The total world market is probably three times that figure, and antibiotics continue to comprise a primary share of the industry. Other principal product categories are enzymes, several organic acids, baker s yeast, ethanol (qv), vitamins (qv), and steroid hormones (qv). 

Unit sales prices of from 800 to 900 fine chemicals are fisted weekly in the Chemical Marketing Reporter. This number reflects those fine chemicals produced and sold in industrial quantities. Some market studies on fine chemicals, fisting important product families, such as side chains for P-lactam antibiotics (qv). A/- and A-heterocycfic compounds, fluoroaromatics, etc, do exist (14,15). 

A number of fungal immunosuppressives have been isolated from fermentation broths and demonstrated to have immunotherapeutic efficacy. Other than cyclosporin (35), two fungal metaboHtes, sirolimus (36), previously known as rapamycin (80), and FK-506 (37) (81) are in various stages of development (see Antibiotics, macrolides). 

Antibiotic and Antimicrobial Drugs. The antimicrobial agents (119) flumequiae (160) and (161), and methylflumequiae (S-25930) (162) and (163) effectively eliminate a number of microbial pathogens via inhibition of the topoisomerase II enzyme of c-DNA containing bacteria (120) (see... 

The sulfa dmgs are stiH important as antimicrobials, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in third world countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim. Their effectiveness has been enhanced by co-adniinistration with dihydrofolate reductase inhibitors, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. 

The number of naturally occurring antibiotics increased from about 30 known in 1945, to 150 in 1949, 450 in 1953, 1200 in 1960, and to 10,000 by 1990 (1,9). Table 1 Hsts the years of historical importance to the development of antibiotics used for treatment in humans. Most of the antibiotics introduced since the 1970s have been derived from synthetic modifications of the P-lactam antibiotics (qv). 

Polyethers. Antibiotics within this family contain a number of cycHc ether and ketal units and have a carboxyHc acid group. They form complexes with mono- and divalent cations that ate soluble ia aoapolar organic solvents. They iateract with bacterial cell membranes and allow cations to pass through the membranes causiag cell death. Because of this property they have been classified as ionophores. Monensia, lasalocid, and maduramicia are examples of polyethers that are used commercially as anticoccidial agents ia poultry and as growth promotants ia mmiaants. 

Most of the new commercial antibiotics have resulted from semisynthetic studies. New cephalosporkis, a number of which are synthesized by acylation of fermentation-derived 7-amkiocephalosporanic acid, are an example. Two orally active cephalosporkis called cefroxadine and cephalexin are produced by a synthetic ring-expansion of penicillin V. 

Antiviral Agents. Although a number of antibiotics have been shown to have some sort of antiviral activity, only vidarabine [5536-17-4] (adenine arabinoside) is used clinically against viral infections at this time. As the need for new antiviral agents (qv) increases and new screening procedures are developed, one would expect the discovery of other new effective antiviral antibiotics that could be used safely in human therapy. 

TicarcHHn [34787-01-4] (SB) (52) is a significant penicillin antibiotic that incorporates the thiophene ring system. A number of routes to the required intermediate, 3-thiophenemalonic acid [21080-92-2] have been used over the years. Those from thiophene-based starting materials have involved 3-methylthiophene and 3-bromothiophene. 

Gonorrhea. Gonorrhea, caused by Neisseriagonorrheae is the most commonly reported communicable disease in the United States. Approximately lO cases were reported to the Center for Disease Control (CDC) in 1979, but actual cases could be two to three times higher (99,100). In addition, an increasing number of strains are becoming resistant to penicillin, the antibiotic that is usually used to treat this disease. 

Many foods such as alcohoHc beverages, pickles, cheese, and fish sauce are preserved by fermentation. Spontaneous fermentations by mixed populations of yeasts and bacteria are normally iavolved. Preservation results from a lowering of pH or the formation of ethanol. Yeasts do not produce antibiotics, although isolates of a number of species produce a toxia ("killer factor") lethal to other yeasts. 

Occurrence, Fermentation, and Biosynthesis. Although a large number of Streptomjces species have been shown to produce carbapenems, only S. cattkja (2) and S. penemfaciens (11) have been reported to give thienamycin (2). Generally the antibiotics occur as a mixture of analogues or isomers and are often co-produced with penicillin N and cephamycin C. Yields are low compared to other P-lactams produced by streptomycetes, and titres are of the order of 1—20 p-g sohdusmL despite, in many cases, a great deal of effort on the optimization of the media and fermentation conditions. The rather poor stabiUty of the compounds also contributes to a low recovery in the isolation procedures. The fermentation and isolation processes for thienamycin and the olivanic acids has been reviewed in some detail (12). 

A number of highly potent DHP-I stable iP-methylcarbapenems having a variety of C-2 substituents have now been described (60,66—69) including SM 7338 [96036-03-2] (42), C yH25N20 S. An acylamiao compound (66) and a iP-methoxy analogue (70) provide other variations. The pyrroHdine substituted iP-methyl-carbapenem SM 7338 (42) is being developed as a broad-spectmm parenteral antibiotic under the name meropenem the synthesis of (42) is by way of the lactone (43) derived by a novel Diels-Alder approach to dihydropyran precursors of (43) (71). 

C QHyN O SNa, as a potentially useful P-lactamase inhibitor capable of potentiating the activity of a number of clinically important P-lactam antibiotics against resistant strains (153). 

Isolation. Isolation procedures rely primarily on solubiHty, adsorption, and ionic characteristics of the P-lactam antibiotic to separate it from the large number of other components present in the fermentation mixture. The penicillins ate monobasic catboxyHc acids which lend themselves to solvent extraction techniques (154). Pencillin V, because of its improved acid stabiHty over other penicillins, can be precipitated dkecdy from broth filtrates by addition of dilute sulfuric acid (154,156). The separation process for cephalosporin C is more complex because the amphoteric nature of cephalosporin C precludes dkect extraction into organic solvents. This antibiotic is isolated through the use of a combination of ion-exchange and precipitation procedures (157). The use of neutral, macroporous resins such as XAD-2 or XAD-4, allows for a more rapid elimination of impurities in the initial steps of the isolation (158). The isolation procedure for cephamycin C also involves a series of ion exchange treatments (103). 

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