Nocardia mediterranei

Rifamycins. The rifamycins were first isolated from a broth of Nocardia mediterranei (the producing organism was originally identified as Streptomyces mediterranei). The rifamycins, the stmctures of which are shown in Figure 3, were originally designated as rifomycins. Only rifamycin B (22), which accounts for 10—15% of the cmde complex, can be isolated easily as a stable, crystalline compound (6,89,90). 

Kanglemycin. Kanglemycia (74) (Fig. 8) is isolated from the fermentation broth filtrate of Nocardia mediterranei var kanglensis (1747-64) and its stmcture determiaed by x-ray crystallographic studies. The antibiotic is active against gram-positive bacteria (28). 

The ansamycins (rifamycin B and rifamycin SV) are produced by certain strains of Nocardia mediterranei and act by inhibition of messenger RNA (m-RNA) synthesis, and consequently of bacterial protein synthesis. Structurally, they present a characteristic ansa structure, made of a ring containing a naphthohydroquinone system spanned by an aliphatic chain. The two ansamycins differ in the type of substituent on the... 

Rifamycin SV (133, Fig. 23) is a naturally occurring macrocycle isolated from Nocardia mediterranei by Senti, Greco and Ballotta in 1959. It shows a high in vitro antibiotic activity through inhibition of DNA-dependent RNA polymerase, but bioavailability is low due to its poor water solubility. The semisynthetic derivative rifampicin (135) displays markedly higher water solubility and in vivo activity. We chose 3-formylrifamycin (134) as model macrocycle for the possibility of binding it to solid phase by hydrazone bond formation in a manner similar to rifampicin (Fig. 24). 

The rifamycins are ansamycin antibiotics produced by cultures of Amycolatopsis mediterranei (formerly Nocardia mediterranei or Streptomyces mediterranei). The crude antibiotic mixture was found to contain five closely related substances rifamycins A-E, but if the organism was cultured in the presence of sodium diethyl barbiturate (barbitone or barbital), the product was almost entirely rifamycin B (Figure 3.71). Rifamycin B has essentially no antibacterial activity, but on standing in aqueous solution in the presence of air, it is readily transformed by oxidation and intramolecular nucleophilic addition into rifamycin O, which... 

The rifamycins were first isolated by Sensi et al.3) from Nocardia mediterranei as a complex mixture (Rifamycins A—E). Addition of diethylbarbiturate to the fermentation medium led to the sole production of rifamycin B6 which was obtained in crystalline form. Its structure has been determined by chemical7,and X-ray analysis9. The rifamycins might easily have excaped detection altogether, since rifamycin B has no antibacterial activity. However, it is spontaneously oxidized to rifamycin 0 and hydrolyzed to rifamycin S, a naphthoquinone derivative reduction yields the naphthohydroquinone derivative rifamycin SV (Fig. 4). These compounds inhibit the growth of Gram-positive bacteria at concentration as low as 0.0025 jug/ml. 

Martinelli, E., Gallo, G.G., Antonini, P. White, R.J. Structure of rifamycin W. A novel ansamycin from a mutant of Nocardia mediterranei. Tetrahedron 30, 3087 (1974)... 

Lancini, G., Sartori, G. Rifamycin G, a further product of Nocardia mediterranei metabolism. J. Antibiotics 29,466 (1976)... 

The other major drug in first-line therapy is rifampicin (Rifampin), which is a chemically modified form of the antibiotic rifamycin B. This was first isolated in 1957 by a group at Lepetit in Milan from a strain of Nocardia mediterranei (also part of the family Actinomycetes) from a soil sample... 

Only Nocardia mediterranei was grown successfully to make possible long term operation of 50 days or more, producing antibiotics rifamycin B with a volumetric productivity of 125 pg/mL/h based on the volume occupied by the immobilized cells. This corresponds to a 30-fold increase over the productivity of a comparable batch system. 

The present study reports the first successful long-term cultivation of rifamycin-B producing Nocardia mediterranei and the problems encountered in growing E. coli and k. niger cells in the dual hollow-fiber bioreactor. 

St. Louis, MO) and Nocardia mediterranei (ATCC 21789) was from American Type Culture Collection. Aspergillus niger B-60 was obtained from Kubicek at Technical University Wien (Austria) who used this strain for citric acid production studies (10.11). 

A model for some rifamycin conversions has been proposed (Scheme 8), based on experimental results with Nocardia mediterranei mutants, conversions of rifamycin n vivo, and the incorporation of different precursors the conversion of rifamycin S (107) into rifamycin B (108) and rifamycin L (109) was completely inhibited by a thiamine antagonist. It was concluded... 

The discovery of rifampicin in 1967 is considered one of the greatest achievements in the history of chemotherapy against tuberculosis. Rifampin was developed in the Lepetit Research Laboratories (Italy) as part of an extensive program of chemical modification of the rifamycins, the natural metabolites of Nocardia mediterranei. All of the studies leading to highly active derivatives were performed on a molecule (rifamycin B) that was itself practically inactive. Systematic structural modifications of most of the functional groups of the rifamycin molecule were... 

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