Maridomycin IV

Maridomycin, a new macrolide antibiotic, and tetrahydromaridomycin were acylated into their mono, di, and tri acyl derivatives. These derivatives were compared with the parent antibiotic, maridomycin, for their (i) in vitro antimicrobial activities, (ii) protective effect in mice infected with Staphylococcus aureus (oral administration), (iii) blood levels attained in rats, and (iv) acute toxicity in mice (intraperitoneal administration). All the derivatives showed either the same or less activity in vitro, but 9-acyl, 9, 2'-diacylmaridomycin and 9, 13, 2'-triacetyltetrahydromaridomycin demonstrated improved therapeutic effects together with higher blood levels and low toxicity. 9-Propionylmaridomycin showed the most favorable biological properties.

Inducible resistance to macrolide, lincosamide, and streptogramin type B antibiotics in Streptomyces spp. comprises a family of diverse phenotypes in which characteristic subsets of the macrolide-lincosamide-streptogramin antibiotics induce resistance mediated by mono- or dimethylation of adenine, or both, in 23S ribosomal ribonucleic acid. In these studies, diverse patterns of induction specificity in Streptomyces and associated ribosomal ribonucleic acid changes are described. In Streptomyces fradiae NRRL 2702 erythromycin induced resistance to vernamycin B, whereas in Streptomyces hygroscopicus IFO 12995, the reverse was found: vernamycin B induced resistance to erythromycin. In a Streptomyces viridochromogenes (NRRL 2860) model system studied in detail, tylosin induced resistance to erythromycin associated with N6-monomethylation of 23S ribosomal ribonucleic acid, whereas in Staphylococcus aureus, erythromycin induced resistance to tylosin mediated by N6-dimethylation of adenine. Inducible macrolide-lincosamide-streptogramin resistance was found in S. fradiae NRRL 2702 and S. hygroscopicus IFO 12995, which synthesize the macrolides tylosin and maridomycin, respectively, as well as in the lincosamide producer Streptomyces lincolnensis NRRL 2936 and the streptogramin type B producer Streptomyces diastaticus NRRL 2560. A wide range of different macrolides including chalcomycin, tylosin, and cirramycin induced resistance when tested in an appropriate system. Lincomycin was active as inducer in S. lincolnensis, the organism by which it is produced, and streptogramin type B antibiotics induced resistance in S. fradiae, S. hygroscopicus, and the streptogramin type B producer S. diastaticus. Patterns of adenine methylation found included (i) lincomycin-induced monomethylation in S. lincolnensis (and constitutive monomethylation in a mutant selected with maridomycin), (ii) concurrent equimolar levels of adenine mono- plus dimethylation in S. hygroscopicus, (iii) monomethylation in S. fradiae (and dimethylation in a mutant selected with erythromycin), and (iv) adenine dimethylation in S. diastaticus induced by ostreogrycin B.

Priopionyl derivatives of maridomycins, 9-propionylmaridomycins (PMDMs), are sixteen-membered ring macrolide antibiotics of six analogous components: I, II, III, IV, V and VI. The present paper deals with the separation and quantitative analysis of these components. The analysis was performed by thin-layer chromatographic separation, addition reaction of gaseous iodine with PMDMs on the plate, extraction of the PMDM-iodine complexes, and subsequent analysis of the amount of reacted iodine, using an automatic analysis system. To ascertain the reaction product of this system, PMDM III-iodine complex was synthesized separately under a liquid-phase reaction and the ratio of PMDM III and iodine atoms was determined to be 1:3 on physicochemical examination.