triostin-a and quinomycin

The physical and biological roles of the cyclic depsipeptides of actinomycin, quinomycin and triostin antibiotic families are proposed by examining the crystal structures of d(GC)-actinomycin D and d(CGTACG)-triostin A. The analyses suggest that not only are DNA-amino acid hydrogen-bonding and chromophore-base pair stacking crucially important for DNA-antibiotic interaction, but also that the unique structure of the cyclic depsipeptides (the perfect hydrophobic character of the inner surface) is equally necessary to insure that these interactions are directed, unambiguous and screened from interference by solvent. Beyond this, the characteristic nature of the outer surfaces suggests a further hypothesis for the biological role of the cyclic depsipeptide rings; when the antibiotics bind in the region around the pause or rho-dependent termination sites on the DNA, the drugs actually terminate transcription by RNA polymerase and cause release of a premature RNA transcript. Termination is likely because the antibiotics carry five to six consecutive apparent A/T sequences on the surface of the cyclic depsipeptide rings, thus presenting a deceptive termination signal to the polymerase.

Topics: Anti-Bacterial Agents; Base Composition; Base Sequence; Dactinomycin; DNA; Echinomycin; Hydrogen Bonding; Molecular Conformation; Quinoxalines; RNA; Structure-Activity Relationship; Transcription, Genetic

Protoplasts of Streptomyces echinatus have been used to investigate the biosynthesis of echinomycin (quinomycin A). It has been shown that this organism has the capacity to convert a series of triostins to the corresponding quinomycins by a mechanism involving methylation. Evidence is presented which suggests that triostin A is the natural precursor of echinomycin. Conversion of tetra-N-demethyl analogues of triostin A to corresponding analogues of echinomycin was not detected.

Topics: Anti-Bacterial Agents; Carbon Radioisotopes; Echinomycin; Kinetics; Protoplasts; Quinoxalines; Streptomyces; Sulfur Radioisotopes

The kinetics of detergent-induced dissociation of triostins A and C and quinomycin C from DNA have been investigated. All three antibiotics dissociate from poly(dA-dT) and poly(dG-dC) in a simple first-order fashion whereas their dissociation from a natural DNA (calf thymus) is complex, requiring three exponential terms for its complete description. This behaviour is attributed to sequence-selectivity on the part of the drugs and seems to represent dissociation from different classes of intercalative binding site. The time constants of dissociation are better resolved for quinomycins than for triostins, consistent with the view that quinomycins are more sequence-specific in their interaction with DNA, but it is not possible to identify any class of binding site with the alternating purine-pyrimidine sequences of the synthetic polydeoxynucleotides. In general, the triostins dissociate an order of magnitude faster than the corresponding quinomycins. This is attributable to a larger entropy of activation, presumably reflecting greater flexibility of the octapeptide ring when the cross-bridge is a disulphide as opposed to the slightly shorter thioacetal found in quinomycins. The longest time constant in the dissociation of each of the four quinoxaline antibiotics from calf thymus DNA correlates well with its antibacterial potency, in agreement with the conclusion that the biological effects result from impairment of the role of DNA as a template for polymerase activity.

Topics: Animals; Anti-Bacterial Agents; Binding Sites; Cattle; DNA; Echinomycin; In Vitro Techniques; Kinetics; Quinoxalines; Structure-Activity Relationship; Thermodynamics