Dotriacolide

A low-mol.-weight DNase inhibitor from M. echinospora was isolated and its activity characterized.The inhibitor produced 50% inhibition of DNase I, DNase II, and DNases from Streptomyces 6016, 4290, and 4098 at concentrations of 6.1, 9, 9.7, 42, and 47 μg.Enzymic activity was inhibited by direct binding of the DNase inhibitor to DNase I; inhibition acted by a mixed type mechanism with K_i ≃3 × 10^-6M.DNA topoisomerase I from adenocarcinoma FM3A cells was completely inhibited (in DNA unwinding) by 2.6 μg/mL of the inhibitor; this was a lower concentration than required for the inhibitors dotriacolide or izumenolide.

A new β-lactamase inhibitor, named dotriacolide (I), was identified and purified from the fermentation broth of Micromonospora echinospora.The dihydro derivative of I, dihydrodotriacolide (II), was also found in this organism.I markedly inhibited penicillinase of Escherichia coli and cephalosporinase of Citrobacter freundii.The ID₅₀ (dose for 50% inhibition) of the Na₄ salt of I was 0.61 μg/mL against penicillinase with benzylpenicillin as substrate and 0.15 μg/mL against cephalosporinase with cephaloridine as substrate.Acute LD₅₀ (dose for 50% lethality) values in mice were 0.18-0.35 mg/kg i.v. and >250 mg/kg orally.By chem. and phys. methods, the structure of the Na₄ salt of I was determined to be (E)-tetrasodium 15,17,29,31,39-pentahydroxy-2-tetracontenoic 1,31-lactone tetrasulfate, and that of the Na salt of II, tetrasodium 15,17,29,31,39-pentahydroxy-2-tetracontanoic 1,31-lactone tetrasulfate.