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Antimicrobial Agents and Chemotherapy, October 1999, p. 2457-2462, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The New Ketolide HMR3647 Accumulates in the Azurophil Granules of Human Polymorphonuclear Cells

Christine Miossec-Bartoli,1,* Lydie Pilatre,1 Pascale Peyron,2 Elsa-Noah N'Diaye,2 Véronique Collart-Dutilleul,1 Isabelle Maridonneau-Parini,2 and Anita Diu-Hercend1

Hoechst Marion Roussel, 93235 Romainville Cedex,1 and Institut de Pharmacologie et de Biologie Structurale, CNRS UPR9062, 31077 Toulouse Cedex,2 France

Received 27 July 1998/Returned for modification 18 November 1998/Accepted 23 July 1999

HMR3647 is a semisynthetic representative of a new group of drugs, the ketolides, derived from erythromycin A. Since macrolides have been shown to accumulate in human polymorphonuclear cells (PMNs), we have investigated the ability of the molecule HMR3647 to enter human PMNs as well as other cell types, such as peripheral blood mononuclear cells and cell lines of hematopoietic and nonhematopoietic origin. In these experiments, HMR3647 was compared to erythromycin A, azithromycin, clarithromycin, and roxithromycin. Our results show that HMR3647 is specifically trapped in PMNs, where it is concentrated up to 300 times. In addition, it is poorly released by these cells, 80% of the compound remaining cell associated after 2 h in fresh medium. By contrast, it is poorly internalized and quickly released by the other cell types studied. This differs from the results obtained with the macrolide molecules, which behaved similarly in the different cells studied. In addition, subcellular fractionation of PMNs allowed us to identify the intracellular compartment where HMR3647 was trapped. In PMNs, more than 75% of the molecule was recovered in the azurophil granule fraction. Similarly, in NB4 cells differentiated into PMN-like cells, almost 60% of the molecules accumulated in the azurophil granule fraction. In addition, when HMR3647 was added to disrupted PMNs, 63% accumulated in the azurophil granules. Therefore, this study shows that the ketolide HMR3647 specifically accumulates in PMN azurophil granules, thus favoring its delivery to bacteria phagocytosed in these cells.

* Corresponding author. Mailing address: Hoechst Marion Roussel, 102 Route de Noisy, 93235 Romainville Cedex, France. Phone: (33) (1) 49 91 47 56. Fax: (33) (1) 49 91 63 80. E-mail: christine.miossec{at}hmrag.com.

Antimicrobial Agents and Chemotherapy, October 1999, p. 2457-2462, Vol. 43, No. 10
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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