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Antimicrobial Agents and Chemotherapy, December 2005, p. 5018-5023, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5018-5023.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Interaction of Rifalazil with Oxidant-Generating Systems of Human Polymorphonuclear Neutrophils

M. T. Labro,1* V. Ollivier,2 and C. Babin-Chevaye1

INSERM U479,1 INSERM U698, CHU Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France2

Received 11 July 2005/ Returned for modification 19 September 2005/ Accepted 26 September 2005

It is well acknowledged that ansamycins display immunosuppressive and anti-inflammatory properties in vitro and in vivo. Rifalazil, a new ansamycin derivative, has not been studied in the context of inflammation. In particular, there are no data on the possible interference of rifalazil with oxidant production by phagocytes. We have compared the antioxidant properties of rifalazil to those of rifampin, a drug well known in this context, by using cellular and acellular oxidant-generating systems. Oxidant production by polymorphonuclear neutrophils was measured in terms of cytochrome c reduction, lucigenin-amplified chemiluminescence (Lu-ACL), and the 2',7'-dichlorofluorescin diacetate H2 (DCFDA-H2) technique (intracellular oxidant production). Rifalazil impaired O2– production in a concentration-dependent manner, with 50% inhibitory concentrations (IC50) (concentrations which inhibit 50% of the response) of 5.4 (30 and 60 min of incubation) and 6.4 (30 min) mg/liter, respectively, for phorbol myristate acetate (PMA) and formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. In agreement with the published fMLP-like activity of rifampin, the inhibitory effect of rifampin was significantly greater for fMLP (IC50 of 5.6 mg/liter) than for PMA (IC50 of 58 mg/liter) stimulation. Alteration of intracellular oxidant production was also observed with IC50 values similar to those obtained by the cytochrome assay. In addition, rifalazil and rifampin (≥25 mg/liter) scavenged O2–, as demonstrated by the acellular (hypoxanthine-xanthine oxidase) system. Interference with light detection systems was evidenced for both drugs by Lu-ACL. The clinical relevance of the antioxidant effect of rifalazil demonstrated in vitro, in particular its potential anti-inflammatory activity, requires further investigation.

* Corresponding author. Mailing address: INSERM U479, CHU Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France. Phone: 33 1 44 85 62 11. Fax: 33 1 44 85 62 07. E-mail: mtlabro{at}wanadoo.fr.

Antimicrobial Agents and Chemotherapy, December 2005, p. 5018-5023, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5018-5023.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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