Kakadumycins, novel antibiotics from Streptomyces sp NRRL 30566, an endophyte of Grevillea pteridifolia.

An endophytic streptomycete (NRRL 30566) is described and partially characterized from a fern-leaved grevillea (Grevillea pteridifolia) tree growing in the Northern Territory of Australia. This endophytic streptomycete produces, in culture, novel antibiotics - the kakadumycins. Methods are outlined for the production and chemical characterization of kakadumycin A and related compounds. This antibiotic is structurally related to a quinoxaline antibiotic, echinomycin. Each contains, by virtue of their amino acid compositions, alanine, serine and an unknown amino acid. Other biological, spectral and chromatographic differences between these two compounds occur and are given. Kakadumycin A has wide spectrum antibiotic activity, especially against Gram-positive bacteria, and it generally displays better bioactivity than echinomycin. For instance, against Bacillus anthracis strains, kakadumycin A has minimum inhibitory concentrations of 0.2-0.3 microg x ml(-1) in contrast to echinomycin at 1.0-1.2 microg x ml(-1). Both echinomycin and kakadumycin A have impressive activity against the malarial parasite Plasmodium falciparum with LD(50)s in the range of 7-10 ng x ml(-1). In macromolecular synthesis assays both kakadumycin A and echinomycin have similar effects on the inhibition of RNA synthesis. It appears that the endophytic Streptomyces sp. offer some promise for the discovery of novel antibiotics with pharmacological potential.

Quinaldopeptin, a novel antibiotic of the quinomycin family.

Quinaldopeptin, a new type of quinomycin antibiotic, was isolated from the culture of Streptoverticillium album strain Q132-6. The antibiotic exhibited strong in vitro antimicrobial and cytotoxic activity and significantly prolonged the survival time of mice inoculated with a murine tumor. Quinaldopeptin is a symmetric cyclic peptide linked only by peptide bonds and differs from known antibiotics of the quinomycin family by the lack of ester linkage.

Liquid chromatographic investigation of quinoxaline antibiotics and their analogues by means of ultraviolet diode-array detection.

Numerical formats for evaluation of spectral purity and for spectral comparison of ultraviolet diode-array detector data, together with library search routines, were applied to the liquid chromatographic analysis of echinomycin, triostin A and their synthetic and biosynthetic analogues. Samples of monoquinoline and bisquinoline analogues of echinomycin were found to contain echinomycin and the other respective analogue. Triostin A and its undermethylated synthetic analogues, des-N-tetramethyltriostin A (TANDEM) and [MeCys3,MeCys7]-TANDEM, were each composed of two or more components. Triostin A primarily consisted of a major chromatographic component and a minor component with very similar ultraviolet spectral features. TANDEM exhibited three chromatographic components with nearly identical ultraviolet spectral characteristics. Apparent conformational interconversion of at least two forms of the [MeCys3,MeCys7]-TANDEM analogue was observed by reversed-phase liquid chromatography. An activation energy of 15 kcal/mol was estimated for the interconversion based upon an Arrhenius plot of the data.

Photofootprinting of drug-binding sites on DNA using diazo- and azido-9-aminoacridine derivatives.

It is demonstrated that DNA photofootprinting analysis of the intercalating depsipeptide echinomycin, and the minor groove-binders distamicyn, 4',6-diamidino-2-phenylindole (DAPI) and Hoechst 33258 can be performed using 9-[6-(2-diazocyclopentadienylcarbonyloxy)hexylamino]acridine (DHA) [Nielsen et al. (1988) Nucleic Acids Res. 16, 3877-3888] or 2-methoxy-6-azido-9-aminoacridine (MAA) [Jeppesen et al. (1988) Nucleic Acids Res. 16, 5755-5770]. Both the extent of the drug-binding sites and their relative strength can be determined with either reagent. DNA has the advantage of giving virtually sequence-uniform DNA photocleavage. On the other hand, structural changes in the DNA are detected by MAA. Using the 232-base-pair EcoRI-PvuII pUC19 restriction fragment, it is found that cleavage protection by distamycin, DAPI and Hoechst 33258 all require an (A.T)4 sequence, whereas protection by echinomycin was confined to a G + C-rich 8-base-pair region.