This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Labro, M. T.
Right arrow Articles by Babin-Chevaye, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Labro, M. T.
Right arrow Articles by Babin-Chevaye, C.

 Previous Article  |  Next Article 

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


arrow
ABSTRACT
 
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.


arrow
INTRODUCTION
 
The immunosuppressive potential of ansamycins and their interference with the immune system are widely acknowledged (14, 15). The antimicrobial activity of ansamycins has been proposed to play a role in the treatment of various inflammatory diseases (including arthritis and Crohn's disease) for which the presence of an underlying pathogen may trigger a chronic inflammatory response. However, the therapeutic effectiveness of ansamycins in inflammatory diseases has also been suggested to rely on their interaction with one or more components of the inflammatory response, among which polymorphonuclear neutrophils (PMN) appear to be critical effectors. NADPH oxidase is the multicomponent enzyme system which reduces oxygen into superoxide anion and H2O2 in a process known as the respiratory burst (29). The oxidative burst is essential for the killing of a number of microorganisms, as shown by the susceptibility to infection of individuals with chronic granulomatous disease (11, 23). However, when oxidants are produced in excess, a detrimental (acute or chronic) inflammatory response may occur. Increase in oxidant production has been associated with and may be causally related to a variety of acute and chronic inflammatory states, such as adult respiratory distress syndrome, hyperoxia, asbestosis, silicosis, ischemia/reperfusion injury, rheumatoid arthritis, cancer, atherosclerosis, cigarette smoking, ionizing radiation, etc. Modulation of oxidant production has become a target for new anti-inflammatory drugs (6, 18). Various antibacterial agents interfere with the phagocyte oxidative burst (16, 17). Many authors have investigated the antioxidant properties of ansamycins. Rifampin, the most important representative of this group, impairs various PMN functions, such as chemotaxis and the oxidative burst (although light-absorbing activity and superoxide anion scavenging can artifactually interact with the detection method) (9, 12, 31). Rifampin inhibits the formyl-methionyl-leucyl-phenylalanine (fMLP)-induced chemiluminescence response of PMN (7) and monocyte oxidative metabolism at therapeutic concentrations (20). Various experimental approaches support the hypothesis that rifampin competes for receptors on neutrophils with small peptide chemoattractants, e.g., fMLP, but not with serum-derived chemoattractants (9) and is a nonchemotactic ligand for fMLP-type receptors (9, 10). Rifampin has also been shown to decrease oxidant production by phagocytes in vivo with animal models (4). In addition, rifamycin SV, rifamycin B, rifampin, and five semisynthetic derivatives impair various human neutrophil functions, including superoxide anion production induced by PMA, although rifamycin SV, rifamycin B, and rifampin are effective only at high concentrations (27, 28). A correlation between improvement of clinical symptoms after treatment of rheumatoid arthritis by local infiltration with rifamycin SV and the impairment of phagocytosis and oxidant production has been suggested (26). Rifalazil, also known as ABI-1648 and KRM-1648, is a new semisynthetic rifamycin with a long half-life of approximately 60 h (24, 25). Originally, rifalazil was developed as a therapeutic agent to replace rifampin as part of a multiple-drug regimen for the treatment of tuberculosis. However, new targets, such as Chlamydia trachomatis, Chlamydia pneumoniae, Clostridium difficile, and Helicobacter pylori, have been proposed (22, 25). The ability of rifalazil to rapidly accumulate in human macrophages, including Mycobacterium avium-infected cells, has been reported (3). Rifalazil has not been studied in the context of inflammation, and there are no data on its interference with oxidant production by phagocytes. In this study, we have compared the antioxidant properties of rifalazil to those of rifampin. PMN were used as the major representative of oxidant-producing cells. To discriminate true antioxidant properties from artifactual results, various acellular oxidant-generating systems were used comparatively.

(These results were presented in part at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., 16 to 19 December 2005 [M. T. Labro and C. Babin-Chevaye, Abstr. 45th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C1-1411, 2005]).


arrow
MATERIALS AND METHODS
 
Ansamycins and reagents. Rifalazil was provided by ActivBiotics (Lexington, MA). Solutions of 1 mg in 5 µl acetic acid (10 N) were made and further diluted in Hanks' balanced salt solution (HBSS) (Sigma, Saint Quentin Fallavier, France) to 1 mg/ml. Further dilutions were made in HBSS to reach the desired final concentrations. Rifampin was from Sigma. Solutions (1 mg/ml) were made in HBSS and further diluted in the same buffer. HBSS was used as the control for the two drugs. All reagents were from Sigma, except where indicated.

Human neutrophils (PMN). PMN were obtained from venous blood of healthy volunteers by Ficoll-Paque centrifugation followed by 2% dextran sedimentation and osmotic lysis of residual erythrocytes. The viability and purity of the PMN preparation, as assessed by trypan blue exclusion, were greater than 96%.

PMN viability. PMN viability was assessed by measuring lactic dehydrogenase (LDH) release by PMN incubated in the presence of rifalazil, rifampin, or control buffer for 30 to 120 min at 37°C.

Superoxide anion production assay. (i) Superoxide anion (O2·–) production was first measured in terms of superoxide dismutase inhibitable cytochrome c reduction by using a Uvikon 860 spectrophotometer (5). PMN (106) were incubated in the presence of rifalazil, rifampin, or control buffer for 30 or 60 min at 37°C before addition of cytochrome c (96 µM) and stimulation with phorbol myristate acetate (PMA) (100 ng/ml) or fMLP (5 x 10–6 M) and cytochalasin B (5 µg/ml). Cytochrome c reduction was monitored at 550 nm (20 readings over 5 min). Paired tests included the same reagents plus superoxide dismutase (SOD) to obtain the true O2·– production. Results are expressed as overall production nmol/min/106 PMN, according to the formula {Delta}OD = {varepsilon} x l x C, where l is the path length of the cuvette (1 cm), C is the concentration of superoxide, {varepsilon} is a constant ({varepsilon} = 21,100 M–1 min–1), and {Delta}OD is the optical density difference.

(ii) Superoxide anion production was also measured in terms of lucigenin (bis-N-methylacridinium nitrate)-amplified chemiluminescence (Lu-ACL) (2). Briefly, 106 PMN were incubated with control buffer or corresponding rifalazil solutions for 30 or 60 min at 37°C in the apparatus in the dark; then, lucigenin (25 µM) was added and cells were stimulated with PMA (100 ng/ml). Chemiluminescence was measured with a chemiluminometer (Autolumat LB953; Berthold, Bad-Wildbad, Germany) for 15 min at 37°C. Paired tests included the same reagents plus SOD (150 U). Results were expressed in terms of overall production (cpm/106 PMN/15 min) and peak of chemiluminescence (cpm/106 PMN/min).

(iii) Intracellular oxidant production was also measured by the 2',7'-dichlorofluorescin diacetate H2 (DCFDA-H2) technique (21). PMN were incubated with the fluorogenic probe DCFDA-H2 (Molecular Probes, Eugene, OR) for 30 min; rifalazil or rifampin was then added for a further 30-min incubation period. The cells were seeded at 100,000 cells/well in polystyrene 96-well culture plates (Falcon; BD Biosciences, Le Pont de Chaix, France); after stimulation with PMA, cells were incubated in the dark at 37°C until fluorescence reading with a microspectrofluorimeter (FLUOstar; BMG Lab Technologies, Champigny/Marne, France) after 5- and 30-min incubations (excitation wavelength [{lambda}ex], 485 nm; emission wavelength [{lambda}em], 530 nm). Controls included cells not labeled with the fluorescent probe (blank), cells not stimulated with PMA (basal level of oxidant production), and cells incubated with the buffer, with/without stimulation with PMA. Results are expressed in arbitrary fluorescence units.

Acellular system. The acellular system (hypoxanthine [HX] plus xanthine oxidase [XO]) was used to measure superoxide anion production by two techniques.

(i) Cytochrome c reduction. HX (0.8 mM), cytochrome c (96 µM), and the drugs were placed in the apparatus (Uvikon 860 spectrophotometer). The reaction was started by the addition of XO (10.8 or 5.4 mU). Readings were made each 15 s over 5 min. Paired tests included the same reagents plus SOD (330 U). Results are expressed as overall production nmol/min/mU, according to the formula given above.

(ii) Lu-ACL. HX (0.8 mM), lucigenin (125 µM), and the drugs were placed in the apparatus. The reaction was started by the addition of XO (0.715 or 0.90 U). Readings were made over 10 min. Paired tests included the same reagents plus SOD (165 U). Results were expressed as indicated above (production and peak).

Statistical analysis. Results are expressed as means ± 1 standard deviation (SD) of the total number of experiments conducted with PMN from different volunteers or the total number of experiments with acellular systems. Experiments with ansamycins are paired with controls (solutions). Analysis of variance was used for multiple comparisons. Paired, normally distributed data were analyzed using the Student t test. Concentration dependence was analyzed by constructing linear or logarithmic regression curves. All statistical tests were run on the Statworks program, version 1.2 (Cricket software, 1985).


arrow
RESULTS
 
(i) Cell viability. Only the concentrations of 100 and 50 mg/liter of rifalazil significantly altered the viability of PMN (Table 1). These concentrations were not used with the cellular assays. At concentrations of ≤25 mg/liter, rifampin did not alter cell viability over 120 min (percentages of LDH release at 30, 60, and 120 min, respectively, were as follows: at 25 mg/liter, 5.5, 7, and 7.5%, versus 3.5, 4.5, and 7.5% for controls, and at 10 mg/liter, 6, 6, and 2%, versus 2, 4, and 9% for controls; means of two experiments).


View this table:
[in this window]
[in a new window]
  		TABLE 1. Effect of rifalazil on PMN viability

(ii) Superoxide anion production assay. (a) Cytochrome c reduction. After PMA stimulation, rifalazil inhibited superoxide anion production in a concentration-dependent manner (Fig. 1A). The effect was not time dependent. Logarithmic regressions were performed to define 50% inhibitory concentrations (IC50) (concentrations which inhibit the response by 50%). IC50 were 5.37 mg/liter (P < 0.001; r = 0.861) and 5.58 mg/liter (P < 0.001; r = 0.892), respectively, at 30 and 60 min. Rifampin displayed a lower inhibitory activity (Fig. 1B), with IC50 of 58 mg/liter at 30 min (P = 0.001; r = 0.793) and 49.7 mg/liter at 60 min (P = 0.004; r = 0.851). Rifalazil impaired superoxide anion production after fMLP stimulation to an extent similar to that observed with PMA (IC50 of 6.4 mg/liter at 30 min) (Fig. 1C). By contrast, the inhibitory effect of rifampin was greater for fMLP stimulation (IC50 of 5.6 mg/liter) than that obtained with PMA.



View larger version (23K):
[in this window]
[in a new window]
  		FIG. 1. Effects of rifalazil and rifampin on superoxide anion production (cytochrome reduction assay). (A and B) PMA stimulation. PMN were incubated for 30 or 60 min with rifalazil (A) or rifampin (B) before stimulation. Results are means ± 1 SD of three to nine experiments (means only for two experiments). Control values (nmol superoxide anion/min/106 PMN) were 6.3 ± 1.91 (nine experiments) for 30 min and 3.8 ± 0.66 (four experiments) for 60 min. (C) fMLP stimulation. PMN were incubated with rifalazil (white columns) or rifampin (stippled columns) for 30 min before stimulation. Results are means ± 1 SD of three to five experiments. Control values (nmol superoxide anion/min/106 PMN) were 6.0 ± 1.91 (seven experiments) for 30 min. *, P of <0.05 versus control (100%).

(b) Control (hypoxanthine-xanthine oxidase system). XO produced about 0.293 ± 0.066 nmol superoxide anion/mU/min (16 experiments). Only high concentrations (50 and 25 mg/liter) of rifalazil scavenged superoxide anion, with about 37% ± 25.2% of control response (four experiments; P = 0.015) at 50 mg/liter and 73% ± 16.6% (seven experiments; P = 0.005) at 25 mg/liter. At 10 mg/liter, 96% ± 19.0% (eight experiments) of control response was obtained. Similar results were obtained with rifampin (at 50 mg/liter, 39% ± 36.7% [five experiments; P = 0.021] and at 25 mg/liter, 89% ± 20.7% [seven experiments; P > 0.05]).

(c) LuACL (PMN). The inhibitory effects of rifalazil and rifampin were also evidenced with the Lu-ACL technique, whatever the parameter measured, overall production (Fig. 2), and peak. For rifalazil, the IC50 calculated by logarithmic regression for overall production and peak, respectively, were 1.12 (P = 0.026; r = 0.525) and 1.70 mg/liter (P = 0.03; r = 0.530) at 30 min and 0.25 mg/liter (P = 0.031; r = 0.621) and 1.0 mg/liter (P = 0.044; r = 0.589) at 60 min. There was no statistical difference between 30 and 60 min. For rifampin, the results gave IC50 of 27.4 mg/liter (P = 0.01) and 28.0 mg/liter (P < 0.001) at 30 min. However, when the drugs were added to the control hypoxanthine-xanthine oxidase system, rifalazil displayed a potent inhibitory effect (IC50 of 1.19 mg/liter for overall production [P < 0.001; r = 0.845] and 0.89 mg/liter for peak [P < 0.001; r = 0.785]), suggesting light-absorbing activities of the blue solution of this drug. For rifampin, IC50 of 40.1 mg/liter for overall production (P < 0.001; r = 0.875) and 44.5 mg/liter for peak (P < 0.001; r = 0.777) were obtained, indicating a moderate light absorption by the yellow solution.



View larger version (13K):
[in this window]
[in a new window]
  		FIG. 2. Effects of rifalazil and rifampin on superoxide anion production (Lu-ACL). PMN were incubated for 30 min with rifalazil (A) or rifampin (B) before stimulation with PMA, or the drug (rifalazil [C] or rifampin [D]) was added to the control acellular system (hypoxanthine-xanthine oxidase). Overall chemiluminescence was measured for 15 min (PMN) or 10 min (hypoxanthine-xanthine oxidase). Results are percentages of control values (means ± 1 SD of three to nine experiments). Control values were 10.8 x 107± 11.2 x 107 cpm/90,000 PMN/15 min (with PMN) and 1.6 x 108± 1.36 x 108 cpm/0.9 U/10 min (with hypoxanthine-xanthine oxidase). *, P of <0.05 versus control (100%). Statistical significance was obtained for all concentrations of rifalazil and for only the highest concentration of rifampin.

(iii) Intracellular oxidant production (DCFDA-H2 technique). The two ansamycins were able to decrease intracellular production of oxidants with IC50 of 14.3 mg/liter (P < 0.001; r = 0.797) and 7.3 mg/liter (P = 0.016; r = 0.675) for rifalazil at 5 and 30 min (P > 0.05 [5 versus 30 min]) and with IC50 of 16 mg/liter (P < 0.001; r = 0.737) and 5.8 mg/liter (P = 0.004; r = 0.760) for rifampin (P < 0.05 [5 versus 30 min]).


arrow
DISCUSSION
 
In this study, we have confirmed that rifampin impairs oxidant production by phagocytes and also interferes with detection systems by scavenging oxidants or by light-absorbing activities, leading to exaggeration of the actual effect. We have also shown that rifalazil displays interesting inhibitory properties by decreasing oxidant production inside and outside the cells. Lu-ACL remains the most sensitive and highly specific test for extracellular superoxide formation in biological systems (1). However, artifactual interferences can be obtained with colored solutions. For this assay, apparent inhibition of superoxide anion production by rifalazil was observed, with IC50 of about 1 mg/liter at 30 min and 60 min of incubation. However, with the control acellular hypoxanthine-xanthine oxidase system, similar IC50 values were obtained, suggesting that light-absorbing activity was responsible for these results (Fig. 2). Rifampin solution also exerted moderate light-absorbing activity (IC50 of about 40 mg/liter). The strong light-absorbing activity of the blue solution of rifalazil renders Lu-ACL inapplicable to analyze its antioxidant activity. The cytochrome c reduction assay has, however, permitted us to characterize the inhibition of rifalazil, which was rapid and did not increase with time, suggesting a rapid cellular uptake. The inhibition was concentration dependent and occurred at concentrations much higher than those obtained in serum. In patients, the peak serum levels after one dose of rifalazil, as measured by the maximum concentration of drug in serum, are about 13.5 and 26.4 ng/ml for the 10- and 25-mg doses, respectively (8), and are higher in normal volunteers (39.3 ng/ml) (24). There are no data on tissue concentrations of rifalazil in humans, but various studies with animals confirm its wide tissue distribution and cell and tissue accumulation (13). The clinical relevance of the inhibitory effects demonstrated in our study still awaits further investigations with cellular and human pharmacokinetics. In particular, it is important to determine whether the inhibitory concentrations that we observed here in vitro may be attained at the sites of the enzymatic reactions, in tissues, or inside cells of subjects who have been administered rifalazil. The inhibitory effect demonstrated with the cytochrome reduction test was not due to scavenging of superoxide anion, which was demonstrated to occur in the acellular system at higher concentrations (50 and 25 mg/liter). The inhibitory effect was not due to cell toxicity either, since only when PMN were exposed to 100 and 50 mg/liter of rifalazil, above the inhibitory concentrations for enzymatic reactions, was viability of PMN an issue. Rifalazil had similar inhibitory actions whatever the stimulus, either PMA, a protein kinase C activator, or fMLP, which triggers a receptor-dependent cascade of intracellular mediators and enzymes. By contrast, rifampin, in agreement with previous data (9, 10), displayed a greater inhibitory activity in the case of fMLP stimulation, likely because of occupancy and blockade of the fMLP receptor. Rifalazil impaired intracellular oxidant production as soon as the first 5 min of incubation, and inhibition did not increase with time. The IC50 was similar to that obtained with the cytochrome assay (extracellular oxidant production). By contrast, rifampin exerted a time-dependent effect, and interestingly, its inhibitory effect was more pronounced in the intracellular assay, with an IC50 10 times lower than that obtained with the cytochrome c test (PMA stimulation, 30-min incubation). DCFH-DA has been widely used to measure the formation of oxidative species in cells. However, the nature of the oxidant responsible for oxidation of DCFH to the fluorescent probe dichlorofluorescein is not clear. Peroxynitrite, hydrogen peroxide, and hydroxyl radical have been designated potential candidates (19). The stronger inhibitory effect of rifampin with this assay system could be related to intracellular scavenging of peroxynitrite, as previously shown for acellular systems (30). Otherwise, intracellular accumulation of the two ansamycins tested here might result in cellular concentrations sufficient to scavenge superoxide anion inside the cells, as observed with the acellular HX-XO system. These hypotheses are difficult to assess. Whatever its origin, decreased intracellular oxidant production may result in diminished bactericidal function of phagocytes. However, this possible defect can be compensated by the potent bactericidal effect of ansamycins themselves and/or the oxygen-independent bactericidal system of phagocytes. Various reports have observed that, despite an impairment of oxidant production by rifampin, the bactericidal function of PMN was not altered (12).

In conclusion, rifalazil impairs superoxide anion production by PMN and this effect is also obtained intracellularly. Whereas this property is unlikely to result in serious bactericidal defects, the possibility that impairment of oxidant production sustains an anti-inflammatory activity should be assessed. The mechanism of inhibition was not studied here and requires further investigation.


arrow
ACKNOWLEDGMENTS
 
This work was supported in part by a grant from ActivBiotics.


arrow
FOOTNOTES
 
* 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. Back


arrow
REFERENCES
 
    1
  1. Afanas'ev, I. B., E. A. Ostrachovitch, and L. G. Korkina. 1999. Lucigenin is a mediator of cytochrome c reduction but not of superoxide production. Arch. Biochem. Biophys. 366:267-274.[CrossRef][Medline]
    2. 2
  2. Aniansson, H., O. Stendhal, and C. Dahlgren. 1984. Comparison between luminol- and lucigenin-dependent chemiluminescence of polymorphonuclear leukocytes. Acta Pathol. Microbiol. Immunol. Scand. Sect. C 92:357-361.[Medline]
    3. 3
  3. Bermudez, L. E., and C. B. Inderlied. 1997. Effect of Mycobacterium avium infection on the influx, accumulation, and efflux of KRM-1648 by human macrophages. Microb. Drug Resist. 3:277-282.[Medline]
    4. 4
  4. Böttcher, T., J. Gerber, A. Wellmer, A. V. Smirnov, F. Fakhrjanali, E. Mix, J. Pilz, U. K. Zettl, and R. Nau. 2000. Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis. J. Infect. Dis. 181:2095-2098.[CrossRef][Medline]
    5. 5
  5. Cohen, H. J., and M. E. Chovaniec. 1978. Superoxide generation by digitonin-stimulated guinea-pig granulocytes. J. Clin. Investig. 61:1081-1087.
    6. 6
  6. Cross, A. R. 1990. Inhibitors of the leukocyte superoxide generating oxidase: mechanisms of action and methods for their elucidation. Free Radic. Biol. Med. 8:71-93.[CrossRef][Medline]
    7. 7
  7. Demkow, U., W. Malkowska-Zwierz, E. Rogala, E. Skopinska-Rozewska, and Z. Lewandowski. 1995. Effect of antituberculous drugs, isoniazid, pyrazinamide and rifampicin, on chemiluminescence of the human polymorphonuclear leukocytes. Folia Biol. (Prague) 41:257-262.
    8. 8
  8. Dietze, R., L. Teixeira, L. M. Rocha, M. Palaci, J. L. Johnson, C. Wells, L. Rose, K. Eisenach, and J. J. Ellner. 2001. Safety and bactericidal activity of rifalazil in patients with pulmonary tuberculosis. Antimicrob. Agents Chemother. 45:1972-1976.[Abstract/Free Full Text]
    9. 9
  9. Gray, G. D., C. W. Smith, J. C. Hollers, D. E. Chenoweth, V. D. Fiegel, and R. D. Nelson. 1983. Rifampin affects polymorphonuclear leukocyte interactions with bacterial and synthetic chemotaxins but not interactions with serum-derived chemotaxins. Antimicrob. Agents Chemother. 24:777-783.[Abstract/Free Full Text]
    10. 10
  10. Gray, G. D., and G. M. Ohlmann. 1986. Countergradients of nonchemotactic ligands for N-formylmethionylleucylphenylalanine (FMLP) receptors promote FMLP-induced chemotaxis. Proc. Soc. Exp. Biol. Med. 181:256-262.[CrossRef][Medline]
    11. 11
  11. Heyworth, P. G., A. R. Cross, and J. T. Curnutte. 2003. Chronic granulomatous disease. Curr. Opin. Immunol. 15:578-584.[CrossRef][Medline]
    12. 12
  12. Hoger, P. H., K. Vosbeck, R. Seger, and W. H. Hitzig. 1985. Uptake, intracellular activity, and influence of rifampin on normal function of polymorphonuclear leukocytes. Antimicrob. Agents Chemother. 28:667-674.[Abstract/Free Full Text]
    13. 13
  13. Hosoe, K., T. Mae, E. Konishi, K. Fujii, K. Yamashita, T. Yamane, T. Hidaka, and T. Ohashi. 1996. Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs. Antimicrob. Agents Chemother. 40:2749-2755.[Abstract]
    14. 14
  14. Labro, M.-T. 2000. Interference of antibacterial agents with phagocyte functions: immunomodulation or "immuno-fairy tales"? Clin. Microbiol. Rev. 13:615-650.[Abstract/Free Full Text]
    15. 15
  15. Labro, M. T. 2005. Antiinflammatory activity of ansamycins. Expert Rev. Anti-Infect. Ther. 3:91-103.[CrossRef]
    16. 16
  16. Labro, M. T. 2004. Antibacterial agents and the oxidative burst, p. 85-106. In B. K. Rubin and J. Tamaoki (ed.), Antibiotics as anti-inflammatory and immunomodulatory agents. Birkhäuser Verlag AG, Basel, Switzerland.
    17. 17
  17. Labro, M. T., and J. El Benna. 1993. Interaction of antibiotics with the phagocyte oxidative burst, p. 953-964. In E. Faist, J. L. Meakins, and F. W. Schildberg (ed.), Host defense dysfunction in trauma, shock and sepsis. Springer-Verlag, Berlin, Germany.
    18. 18
  18. Miesel, R., D. Sanocka, M. Kurpisz, and H. Kröger. 1995. Antiinflammatory effects of NADPH oxidase inhibitors. Inflammation 19:347-362.[CrossRef][Medline]
    19. 19
  19. Myhre, O., J. M. Andersen, H. Aarnes, and F. Fonnum. 2003. Evaluation of the probes 2',7'-dichlorofluorescein diacetate, luminol, and lucigenin as indicators of reactive species formation. Biochem. Pharmacol. 65:1575-1582.[CrossRef][Medline]
    20. 20
  20. Nielsen, H. 1989. Antibiotics and human monocyte function. II. Phagocytosis and oxidative metabolism. APMIS 97:447-451.[Medline]
    21. 21
  21. Plantin-Carrenard, E., F. Braut-Boucher, M. Bernard, C. Derappe, M. J. Foglietti, and M. Aubery. 2000. Fluorogenic probes applied to the study of induced oxidative stress in the human leukaemia HL 60 cell line. J. Fluoresc. 10:167-176.
    22. 22
  22. Roblin, P. M., T. Reznik, A. Kutlin, and M. R. Hammerschlag. 2003. In vitro activities of rifamycin derivatives ABI-1648 (rifalazil, KRM-1648), ABI-1657, and ABI-1131 against Chlamydia trachomatis and recent clinical isolates of Chlamydia pneumoniae. Antimicrob. Agents Chemother. 47:1135-1136.[Abstract/Free Full Text]
    23. 23
  23. Roos, D., R. van Bruggen, and C. Meischl. 2003. Oxidative killing of microbes by neutrophils. Microbes Infect. 5:1307-1315.[CrossRef][Medline]
    24. 24
  24. Rose, L. M., M. K. Vasiljev, P. Adams, V. Mizuno, C. Wells, and A. B. Montgomery. 1999. Safety and pharmacokinetics of PA-1648, a new rifamycin in normal volunteers. Am. J. Respir. Crit. Care Med. 159(Suppl.):A495.
    25. 25
  25. Rothstein, D. M., A. D. Hartman, M. H. Cynamon, and B. I. Eisenstein. 2003. Development potential of rifalazil. Expert Opin. Investig. Drugs 12:255-271.[CrossRef][Medline]
    26. 26
  26. Spisani, S., L. Dovigo, G. Corazza, R. Carletti, and S. Traniello. 1982. The effect of rifamycin SV on neutrophil functions in patients with rheumatoid arthritis. Scand. J. Rheumatol. 11:65-69.[Medline]
    27. 27
  27. Spisani, S., S. Traniello, C. Martuccio, O. Rizzuti, and L. Cellai. 1997. Rifamycins inhibit human neutrophil functions: new derivatives with potential antiinflammatory activity. Inflammation 21:391-400.[CrossRef][Medline]
    28. 28
  28. Spisani, S., S. Traniello, A. M. Onori, O. Rizzuti, C. Martuccio, and L. Cellai. 1998. 3-(Carboxyalkylthio) rifamycin S and SV derivatives inhibit human neutrophil functions. Inflammation 22:459-469.[CrossRef][Medline]
    29. 29
  29. Vignais, P. V. 2002. The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell. Mol. Life Sci. 59:1428-1459.[CrossRef][Medline]
    30. 30
  30. Whiteman, M., and B. Halliwell. 1997. Prevention of peroxynitrite-dependent tyrosine titration and inactivation of alpha1 antiproteinase by antibiotics. Free Radic. Res. 26:49-56.[Medline]
    31. 31
  31. Zeis, B. M. 1988. Antimycobacterial drugs and the production of reactive oxidants by polymorphonuclear leucocytes in vitro. Chemotherapy 34:56-60.[Medline]

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.




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Labro, M. T.
Right arrow Articles by Babin-Chevaye, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Labro, M. T.
Right arrow Articles by Babin-Chevaye, C.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»