Macrolide antibiotics discovery

Discovery and development of a novel immunosuppressant. Tacrolimus hydrate (FK-506), macrolide antibiotic with piperidine and tetrahydrofuran fragments 97YZ542. 

Discovery research, on macrolide antibiotics, 15 305-306 Discrete optimization problems,... 

One of the most famous examples of intramolecular attack of oxygen on the nitriUnm ion intermediate was observed in the Beckmann rearrangement of Erythromycin oxime derivatives and was used in the discovery and synthesis of the commercial macrolide antibiotic Azithromycin 464. In fact, the Beckmann rearrangement of Erythromycin A 9( )-oxime 460 produced only small amounts (5%) of the expected amide 463, along with two isomeric imino ethers (461 and 462) in a fair yield (38 and 43%) (equation 198). 

This precise sequence was discovered only through very careful double labelling experiments and after the discovery of specific inhibitors for the enzyme. Since polyketides can be made from the acyl polymalonate pathway with or without reduction and elimination at any step, the number of possible structures is vast. With more reduction, no aromatic ring can be formed macrolide antibiotics such as brefeldin A come from this route. 

After the Second World War, the effort continued to find other novel antibiotic structures. This led to the discovery of the peptide antibiotics (e.g. bacitracin (1945)), chloramphenicol (Fig. 10.72) (1947), the tetracycline antibiotics (e.g. chlortetracycline (Fig. 10.71) (1948)), the macrolide antibiotics (e.g. erythromycin (Fig. 10.73) (1952)), the cyclic peptide antibiotics (e.g. cycloserine (1955)), and in 1955 the first example of a second major group of (3-lactam antibiotics, cephalosporin C (Fig. 10.41). 

Polyenes - The occurrence, production, and sources of polyene macrolide antibiotics have been summarizedThe discovery that the antifungal action of polyenes is associated with... 

Kahan JS, Kahan FM, Geogelman R, Currie SA, Jackson M, Stapley EO, Miller TW, Hendlin D, Mochales S, Hernandez S, Woodruff HB, Birnbaum J (1979) Thienamycin, a new P-lactam antibiotic discovery, taxonomy, isolation, and physical properties. J Antibiot 32 1-12 Kao CM, Luo G, Katz L, Cane DE, Khosla C (1995) Manipulation of macrolide ring size by directed mutagenesis of a modular polyketide synthase. J Am Chem Soc 117 9105-9106... 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

Further antibiotics, mainly derived from actinomycetes, are used for special applications in human and veterinary medicine [20]. These compounds have numerous chemical structures. The macrolides, tetracyclines, aminoglycosides, glycopeptides, and ansamycins for instance are used in antibacterial treatment whereas the anthracyclines reached the market to supplement anticancer chemotherapy. The fairly toxic polyether-type antibiotics are preferably used as anticoccidial agents. Due to the dramatically increasing resistance of clinical important bacterial strains new targets for the discovery of novel types of antibacterial agents are urgently needed. 

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