title: Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis.
abstract: Mycobacterium tuberculosis is an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 microg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.
authors.affiliation: Institute of Clinical Immunology SD RAMS, Novosibirsk, Russia.
authors.forename: Y S
authors.initials: YS
authors.lastname: Schwartz
authors.forename: M I
authors.initials: MI
authors.lastname: Dushkin
authors.forename: V A
authors.initials: VA
authors.lastname: Vavilin
authors.forename: E V
authors.initials: EV
authors.lastname: Melnikova
authors.forename: O M
authors.initials: OM
authors.lastname: Khoschenko
authors.forename: V A
authors.initials: VA
authors.lastname: Kozlov
authors.forename: A P
authors.initials: AP
authors.lastname: Agafonov
authors.forename: A Y
authors.initials: AY
authors.lastname: Alekseev
authors.forename: Y
authors.initials: Y
authors.lastname: Rassadkin
authors.forename: A M
authors.initials: AM
authors.lastname: Shestapalov
authors.forename: M S
authors.initials: MS
authors.lastname: Azaev
authors.forename: D V
authors.initials: DV
authors.lastname: Saraev
authors.forename: P N
authors.initials: PN
authors.lastname: Filimonov
authors.forename: Y
authors.initials: Y
authors.lastname: Kurunov
authors.forename: A V
authors.initials: AV
authors.lastname: Svistelnik
authors.forename: V A
authors.initials: VA
authors.lastname: Krasnov
authors.forename: A
authors.initials: A
authors.lastname: Pathak
authors.forename: S C
authors.initials: SC
authors.lastname: Derrick
authors.forename: R C
authors.initials: RC
authors.lastname: Reynolds
authors.forename: S
authors.initials: S
authors.lastname: Morris
authors.forename: V M
authors.initials: VM
authors.lastname: Blinov
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001372:Aza Compounds / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015169:Colony Count, Microbial; D003619:Dansyl Compounds / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D024841:Fluoroquinolones; D005936:Glucans / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D006207:Half-Life; D066298:In Vitro Techniques; D016676:Macrophages, Alveolar / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011804:Quinolines / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D000995:Antitubercular Agents; D001372:Aza Compounds; D003619:Dansyl Compounds; D024841:Fluoroquinolones; D005936:Glucans; D011804:Quinolines; D000077266:Moxifloxacin