Preparation and DNA-binding properties of substituted triostin antibiotics

Abstract

Novel derivatives of the triostin group of antibiotics were prepared by supplementing cultures of the producing organism Streptomyces triostinicus with a variety of aromatic carboxylic acids. Five new antibiotics, each having both the natural quinoxaline chromophores replaced by a substituted ring system, were purified to homogeneity and characterized by high-pressure liquid chromatography and nuclear magnetic resonance. Their antibacterial activities and DNAbinding properties were investigated. Addition of a halogen atom at position 6 of the quinoxaline ring or an amino group at position 3 had little effect on either the biological activity or the DNA-binding characteristics. The bis-3-amino derivative is fluorescent, and its fluorescence is strongly quenched by calf thymus DNA and polydeoxyguanylate-polydeoxycytidylate but not by polydeoxyadenylatepolydeoxythymidylate, suggesting that it binds preferentially to guanosine-cytosine-rich sequences in natural DNA. Binding constants for the bis-6-chloro and bis-3-amino derivatives do not differ greatly from those of unsubstituted triostin A. The analogs having two quinoline chromophores or a chlorine atom in position 7 of the quinoxaline ring display little or no detectable antibacterial activity, in marked contrast to the other congeners. Bis-7-chloro-triostin A binds conspicuously more tightly to polydeoxyadenylate-polydeoxythymidylate than to any other polynucleotide tested.Quinoxaline antibiotics are produced by several species of streptomycetes. They are characterized by a heterodetic cyclic octadepsipeptide to which two quinoxaline-2-carboxylic acid chromophores are attached. Members of the group fall naturally into two families, the quinomycins and the triostins, which differ in the nature of the cross-bridge dividing the peptide ring into two quasi-symmetrical halves (11, 21). The triostins possess a simple disulfide crossbridge (Fig.

Binding Kinetics of Bisintercalator Triostin A with Optical Tweezers Force Mechanics

“…Our method provides comparable results for the force dependence of the association constant to the results presented for ethidium (11). The derived zero force binding constant of K 0 ¼ (5.8 5 0.3) Â 10 5 M À1 compares favorably with a previously published value of K A (at F ¼ 0) z 10 6 M À1 , which was determined by a solvent partition method (8,9).…”

“…As a member of the quinoxaline family of antibiotics, Triostin A consists of a cyclic disulfide bridged backbone with two covalently linked quinoxalines that are well oriented for bisintercalation in dsDNA ( Fig. 1 a) (8,9).…”

Recent developments in bisintercalator natural products

“…Early feeding studies in S. triostinicus and S. echinatus using several structural analogs of QXC revealed that QXC acted as a free intermediate during triostin A and echinomycin biosynthesis 48, 58–61. In line with this observation, Keller and coworkers isolated and characterized the enzyme that activates QXC to QXC‐AMP in S. triostinicus and S. echinatus 62.…”

Heterocycles [h]-Fused onto 4-Oxoquinoline-3-carboxylic Acid, V [1]. Synthesis and Antibacterial Activity of Some New 2,3-Disubstituted 7-Oxo-7,10-dihydropyrido[2,3-f]quinoxaline-8-carboxylic Acids and Esters

“…Several synthetic and naturally occurring compounds containing the quinoxaline ring system were reported to exhibit a broad spectrum of biological activities including antitumor [5], anti-HIV [6], antimicrobial [7], antiprotozoal [8], antifungal [9], antibiotic [10,11], and human cyclophilin A inhibitor [12] properties. On the other hand, synthetic second generation fluoroquinolones (e. g. ciprofloxacin) [13] have recently emerged as potent antiinfectious drugs [13,14].…”