New fluorinated erythromycins obtained by mutasynthesis.

Abstract

Following the previously described semisynthetic preparation of new aglycones (8S)-8fluoroerythronolide A (I), (8S)-8-fluoroerythronolide B (II) and the monoglycoside 3-0mycarosyl-(8S)-8-fluoroerythronolide B (III), their conversion into new fluoroerythromycins was attempted by mutational biosynthesis. The strain Streptomyces erythraeus ATCC 31772, a mutant blocked in the biosynthesis of erythromycin, was employed in the present investigation. Four new antibiotics, (8S)-8-fluoroerythromycin A (IV), (8S)-8-fluoroerythromycin B (V), (8S)-8-fluoroerythromycin C (VI) and (8S)-8-fluoroerythromycin D (VII) were successfully derived by such an approach. The result is also discussed in terms of the substrate specificity of the enzymes involved in the biosynthesis of erythromycins. The new antibiotics exhibited promising biological properties. During the last twenty years advances in organic fluorine chemistry have been responsible for the development of a large number of new compounds of importance in biology and medicine. Replacement of an atom of hydrogen by one of fluorine in organic molecules may profoundly change their biological properties','). The rationale employed is that, since hydrogen and fluorine are nearly isosteric, the fluoro analog would be expected to have little difficulty in fitting onto active sites of receptors. At the same time, the strong electronegativity of the fluorine atom, when strategically placed, could be used to make defined alterations in the biological activity.

New directions for macrolide antibiotics: structural modifications and in vitro activity

“…Although few publications have reported the antibacterial activity of flurithromycin, it appears to be very similar to erythromycin in vitro (41); activity against staphylococci, streptococci, H. influenzae, and B. catarrhalis was approximately the same as that of erythromycin (37,61,76). One study reported some improvement in activity against anaerobic bacteria (37).…”

Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides

“…Since its introduction in 1952 (25). A-62671 is the major metabolite of clarithromycin in humans, and dirithromycin is a prodrug of erythromycylamine.…”

Metabolism of fluoroorganic compounds in microorganisms: impacts for the environment and the production of fine chemicals

“…In one study, semi-synthetic erythromycin aglycones were fed to a Saccharopolyspora erythraea (Streptomyces erythraeus) strain blocked in erythromycin production, leading to the production of 8-fluoroerythromycins (Toscano et al 1983). These novel analogues possessed comparable antibiotic activity to the parent compounds, but higher levels were present in the serum and tissue (Benoni et al 1988).…”