Scientific Publications by FDA Staff

Antimicrob Agents Chemother 2006 Jun;50(6):1982-8

Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity against Mycobacterium tuberculosis.

Schwartz YS, Dushkin MI, Vavilin VA, Melnikova EV, Khoschenko OM, Kozlov VA, Agafonov AP, Alekseev AY, Rassadkin Y, Shestapalov AM, Azaev MS, Saraev DV, Filimonov PN, Kurunov Y, Svistelnik AV, Krasnov VA, Pathak A, Derrick SC, Reynolds RC, Morris S, Blinov VM

Morris S, US FDA, Ctr Biol Evaluat & Res, Bldg 29,Room 502,29 Lincoln Dr, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA RAMS, SD, Inst Clin Immunol, Novosibirsk, Russia Russian Minist Publ Hlth, State Res Ctr Virol & Biotechnol Vector, Koltsov, Novosibirsk, Russia Russian Minist Publ Hlth, Novosibirsk Inst TB, Novosibirsk, Russia So Res Inst, Birmingham, AL 35255 USA

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 mug/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.