Heterologous expression of oxytetracycline biosynthetic gene cluster in Streptomyces venezuelae WVR2006 to improve production level and to alter fermentation process.

Heterologous expression is an important strategy to activate biosynthetic gene clusters of secondary metabolites. Here, it is employed to activate and manipulate the oxytetracycline (OTC) gene cluster and to alter OTC fermentation process. To achieve these goals, a fast-growing heterologous host Streptomyces venezuelae WVR2006 was rationally selected among several potential hosts. It shows rapid and dispersed growth and intrinsic high resistance to OTC. By manipulating the expression of two cluster-situated regulators (CSR) OtcR and OtrR and precursor supply, the OTC production level was significantly increased in this heterologous host from 75 to 431 mg/l only in 48 h, a level comparable to the native producer Streptomyces rimosus M4018 in 8 days. This work shows that S. venezuelae WVR2006 is a promising chassis for the production of secondary metabolites, and the engineered heterologous OTC producer has the potential to completely alter the fermentation process of OTC production.

A terramicina na lepra

Antibiotics, in the authors' opinion, represent a very promising group of drugs against lepromatous leprosy, although the most neglected. Tetracycline group has been known for its broad spectrum of acitivity, a low toxicity rate and a slowly developing type of resistance. All the references in the literature concerning the use of antibiotics in leprosy show how very irregular have been the periods of treatment, the dosage employed, the conditions under which trials were conducted in each group, as well as the lack of uniformity in the choosing of patients and the carryng out of the studies, all this yielding as could not have been otherwise, a disparity of conclusions. In 1964, Mariano, from Belo Horizonte (Brazil) reported good results in the treatment of lepromatous and tuberculoid cases with intramuscular Terramycin at a dosage of 100 mg every 48 hours. Encoureaged by these results the authors undertook a long-term study oxytetracycline in lepromatous leprosy. Twenty-two patients were included and Terramycin pre-constituted solution was applied by intramuscular route in dosages of 100 mg every 12 hours, during 12 months or so. For therapeutic control the test indicated below were performed. 1. Dermatological examination at the beginning ot treatment and on monthly intervals; 2. Bacilloscopic examination of mucus and skin lesions at the beginning of treatment, and on monthly; 3. Histopathological examination of biopsies taken at the beginning of treatment, and 6 and 12 months thereafter; 4. Color photos on starting treatment and 6 months later, eventually even every month. Nineteen patient presented circunscribed lesions with predominant papules, tubercles and nodules. Thw reamaining theree cases had erythema and diffuse infiltration. All of the 22 patients treated with oxytetracycline improved clinically. On the average, imoprovement took place between the first and the third month of treatment; from there on, involution of the lesions slowed down...