John C. Godfrey

Effect of Structural Modifications on the Biological Properties of Aminoglycoside Antibiotics Containing 2-Deoxystreptamine

Publisher Summary This chapter summarizes the current status of knowledge about structure-activity relationships of 2-deoxystreptamine (DOS)-containing aminoglycosides, and emphasizes on the recent advances in this field that are likely to result in development of clinically superior aminoglycoside antibiotics. The first 2-DOS-containing antibiotics discovered were the neomycins. The producing organism was isolated in 1949 from soil and was subsequently given the designation streptomyces fradiae. The chapter examines the relationships between the structures of a number of naturally produced and semi-synthetic aminoglycoside antibiotics and their intrinsic antimicrobial activity, the breadth of their antimicrobial spectrum, and their inherent toxicity for mammals. The relative capability of the compounds to inhibit protein synthesis in a cell-free system when used at a standard concentration is considered. Intrinsic antimicrobial potency is estimated by utilizing MIC results obtained with several representative aminoglycoside-sensitive bacterial species in 2-fold serial dilution assays. Since 2-DOS has no antibiotic activity itself, it must be substituted with one or more glycosidic moieties in order to acquire antimicrobial properties. The chapter also discusses the role played by the amines that are present in the C-4-substituent of 2-DOS.

Structure-Activity Relationships in Coumermycins

Publisher Summary This chapter focuses on the structure–activity relationships in coumermycins. The naturally occurring coumermycins are produced in fermentation broths of several species of Streptomyces . Degradative studies at Bristol–Banyu Research Institute established the structures of coumermycins A 1 and A 2 . Several bioactive components, including coumermycin A 1 , were elaborated by Streptomyces rishiriensis, which was isolated from a soil sample collected in Rishiri Island, Hokkaido, Japan. Another Streptornyces isolate, originally designated as species X-7763 by the Hoffmann–LaRoche group, was obtained from a soil sample collected in Gaspe, Canada. It was also found to produce multiple antibiotics, each containing a coumarin-like moiety. Chromatographic and degradative studies revealed the fact that the antibacterial activity of the culture filtrates was attributable to a number of closely related substances. Among the naturally produced coumermycins, the degree of methylation of the terminal pyrrole moities and the presence or absence of this heterocyclic function correlates positively with intrinsic biopotency and vary probably with breadth of antimicrobial spectrum.

The Coumermycins: Developments in the Late 1970s

Publisher Summary The investigation of the steps in the biosynthesis of coumermycin have proved that δ-aminolevulinic acid is the precursor for the central 3-methylpyrrole-2,4-dicarboxylic acid of the coumermycins. It has also proved that proline is the precursor of the terminal pyrrole-2-carboxylic esters. In 1977, results from an investigation of the inhibition of DNA gyrase by nalidixic and oxolinic acids, were reported. It was found that the enzyme is inhibited by both of these acids, but that oxolinic acid is much more potent than nalidixic acid. The locus of action of oxolinic acid is entirely different from that of coumermycin A 1 . No cross-resistance was found between oxolinic acid inhibition and coumermycin A 1 inhibition of E. coli DNA gyrase. It was further discovered that in the absence of ATP and with a high concentration (6 mM) of magnesium ion, DNA gyrase will transform supercoiled DNA to the relaxed form, in exact opposition to what DNA gyrase usually does.