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Antimicrobial Agents and Chemotherapy, June 2006, p. 1982-1988, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00362-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity against Mycobacterium tuberculosis{dagger}

Y. S. Schwartz,1 M. I. Dushkin,1 V. A. Vavilin,1 E. V. Melnikova,1 O. M. Khoschenko,1 V. A. Kozlov,1 A. P. Agafonov,2 A. Y. Alekseev,2 Y. Rassadkin,2 A. M. Shestapalov,2 M. S. Azaev,2 D. V. Saraev,2 P. N. Filimonov,3 Y. Kurunov,3 A. V. Svistelnik,3 V. A. Krasnov,3 A. Pathak,4 S. C. Derrick,5 R. C. Reynolds,4 S. Morris,5* and V. M. Blinov2

Institute of Clinical Immunology SD RAMS, Novosibirsk, Russia,1 State Research Center of Virology and Biotechnology Vector, Russian Ministry of Public Health, Koltsovo, Novosibirsk Region, Russia,2 Novosibirsk Institute of Tuberculosis, Russian Ministry of Public Health, Novosibirsk, Russia,3 Southern Research Institute, Birmingham, Alabama,4 FDA/CBER, Bethesda, Maryland5

Received 18 March 2005/ Returned for modification 6 April 2005/ Accepted 28 March 2006

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 µg/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.

* Corresponding author. Mailing address: Building 29/Room 502, FDA/CBER, 29 Lincoln Dr., Bethesda, MD 20892. Phone: (301) 496-5978. Fax: (301) 435-5675. E-mail: morris{at}cber.fda.gov.

{dagger} Supplemental material for this article may be found at http://aac.asm.org/.

Antimicrobial Agents and Chemotherapy, June 2006, p. 1982-1988, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00362-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Yew, W. W., Leung, C. C. (2007). Update in Tuberculosis 2006. Am. J. Respir. Crit. Care Med. 175: 541-546 [Full Text]  


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