Macrolide antibiotics have an outstanding ability to concentrate within host cells, particularly phagocytes. In the study described in this paper five different macrolide antibiotics were compared regarding the uptake and release kinetics in human peripheral blood polymorphonuclear neutrophils (PMNs) and three different cell lines, two phagocytic cell lines (RAW 264.7 and THP-1) and an epithelial cell line (MDCK). Based on the results obtained, the substances tested could be clustered into different groups. Azithromycin constituted the first group, characterized by rapid and nonsaturable uptake into phagocytic cells and a high degree of retention in the preloaded cells. The second group included erythromycin and clarithromycin. These two substances do not exhibit cell specificity; consequently, they are taken up to a similar extent and are released by all cell types studied. Ketolides constituted the last group. Their uptake was saturable in cells of monocytic lineage as well as in nondifferentiated cells of myeloid lineage, and they were rapidly released from all the cell lines studied. However, in PMNs, ketolide uptake was not saturable; and unlike telithromycin, cethromycin rapidly egressed from the loaded cells.
4'-Deoxy-10,l l ,12,1 3-tetrahydrodesmycosin was prepared in six-step reactions. Antibacterial screening shows retained antibacterial spectrum of tylosin with some improvementagainst tylosin-sensitive Staphylococci and Haemophilus influenze. However,pharmacokinetic data demonstrated rapid distribution from blood in tissues and prolonged maintenance in all tissues, especially in the lungs, in comparison with tylosin. 10,1 1,12,13-Tetrahydrodesmycosin, a 16-membered macrolide antibiotic is obtained by selective catalytic hydrogenation of desmycosin in the C-10, C-ll, C-12, C-13 position, or by mild acid hydrolysis of previously prepared 10, 1 l^n-tetrahydrotylosm1). 1 6-Membered macrolides: rosamycin2) and mycinami-cins3) with desosamine (4/-deoxy-mycaminose) in the C-5 position instead of mycaminose,were found to be active against some strains of Gram-negative and macrolide resistent Gram-positive bacteria. Deoxygenation of C-4' hydroxyl group of desmyco-sin40, 1 9-deformyl-desmycosin5) or related 1 6-membered macrolide, neospiramycin6), has already been accomplished. In preceding papers4'5) it was shown that the 4'-deoxy derivatives of desmycosin exhibit enhanced activity in comparison to those of corresponding 4'hydroxy compounds. Contrary to expectation C-4'
bAs we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo. MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds. In vivo efficacy was assessed in a murine model of S. pneumoniae-induced pneumonia, and pharmacokinetic (PK) profiles in mice were determined. The in vitro antibacterial profiles of macrolones were superior to those of marketed macrolide antibiotics, including the ketolide telithromycin, and the compounds did not induce the expression of inducible erm genes. They acted as typical protein synthesis inhibitors in an Escherichia coli transcription/translation assay. Macrolones were characterized by low to moderate systemic clearance, a large volume of distribution, a long half-life, and low oral bioavailability. They were highly efficacious in a murine model of pneumonia after intraperitoneal application even against an S. pneumoniae strain with constitutive resistance to macrolide-lincosamide-streptogramin B antibiotics. Macrolones are the class of macrolide antibiotics with an outstanding antibacterial profile and reasonable PK parameters resulting in good in vivo efficacy.
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