[en] Probing drug/lipid interactions at the molecular level represents an important challenge in pharmaceutical research and membrane biophysics. Previous studies showed differences in accumulation and intracellular activity between two fluoroquinolones, ciprofloxacin and moxifloxacin, that may actually result from their differential susceptibility to efflux by the ciprofloxacin transporter. In view of the critical role of lipids for the drug cellular uptake and differences observed for the two closely related fluoroquinolones, we investigated the interactions of these two antibiotics with lipids, using an array of complementary techniques. Moxifloxacin induced, to a greater extent than ciprofloxacin, an erosion of the DPPC domains in the DOPC fluid phase (atomic force microscopy) and a shift of the surface pressure-area isotherms of DOPC/DPPC/fluoroquinolone monolayer toward lower area per molecule (Langmuir studies). These effects are related to a lower propensity of moxifloxacin to be released from lipid to aqueous phase (determined by phase transfer studies and conformational analysis) and a marked decrease of all-trans conformation of acyl-lipid chains of DPPC (determined by ATR-FTIR) without increase of lipid disorder and change in the tilt between the normal and the germanium surface (also determined by ATR-FTIR). All together, differences of ciprofloxacin as compared to moxifloxacin in their interactions with lipids could explain differences in their cellular accumulation and susceptibility to efflux transporters.
Michot, J. M., C. Seral, F. Van Bambeke, M. P. Mingeot-Leclercq, and P. Tulkens. 2005. Influence of efflux transporters on the accumulation and efflux of four quinolones (ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin) in J774 macrophages. Antimicrob. Agents Chemother. 49:2429-2437.
Bakker-Woudenberg, I. A., M. T. ten Kate, L. Guo, P. Working, and J. W. Mouton. 2001. Improved efficacy of ciprofloxacin administered in polyethylene glycol-coated liposomes for treatment of Klebsiella pneumoniae pneumonia in rats. Antimicrob. Agents Chemother. 45:1487-1492.
Bakker-Woudenberg, I. A., M. T. ten Kate, L. Guo, P. Working, and J. W. Mouton. 2002. Ciprofloxacin in polyethylene glycol-coated liposomes: efficacy in rat models of acute or chronic Pseudomonas aeruginosa infection. Antimicrob. Agents Chemother. 46:2575-2581.
Wong, J. P., H. Yang, K. L. Blasetti, G. Schnell, J. Conley, and L. N. Schofield. 2003. Liposome delivery of ciprofloxacin against intracellular Francisella tularensis infection. J. Control. Release. 92:265-273.
Rolston, K. V., D. Yadegarynia, D. P. Kontoyiannis, I. I. Raad, and D. H. Ho. 2006. The spectrum of Gram-positive bloodstream infections in patients with hematologic malignancies, and the in vitro activity of various quinolones against Gram-positive bacteria isolated from cancer patients. Int. J. Infect. Dis. 10:223-230.
Bounds, S. J., R. Nakkula, and J. D. Walters. 2000. Fluoroquinolone transport by human monocytes: characterization and comparison to other cells of myeloid lineage. Antimicrob. Agents Chemother. 44:2609-2614.
Hirota, M., T. Totsu, F. Adachi, K. Kamikawa, J. Watanabe, S. Kanegasaki, and K. Nakata. 2001. Comparison of antimycobacterial activity of grepafloxacin against Mycobacterium avium with that of levofloxacin: accumulation of grepafloxacin in human macrophages. J. Infect. Chemother. 7:16-21.
Hara, T., H. Takemura, K. Kanemitsu, H. Yamamoto, and J. Shimada. 2000. Comparative uptake of grepafloxacin and ciprofloxacin by a human monocytic cell line, THP-1. J. Infect. Chemother. 6:162-167.
Seral, C., M. Barcia-Macay, M. P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke. 2005. Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin) against extracellular and intracellular infection by Listeria monocytogenes and Staphylococcus aureus in J774 macrophages. J. Antimicrob. Chemother. 55:511-517.
Fresta, M., S. Guccione, A. R. Beccari, P. M. Furneri, and G. Puglisi. 2002. Combining molecular modeling with experimental methodologies: mechanism of membrane permeation and accumulation of ofloxacin. Bioorg. Med. Chem. 10:3871-3889.
Michot, J. M., F. Van Bambeke, M. P. Mingeot-Leclercq, and P. M. Tulkens. 2004. Active efflux of ciprofloxacin from J774 macrophages through an MRP-like transporter. Antimicrob. Agents Chemother. 48:2673-2682.
Fernandez-Teruel, C., I. Gonzalez-Alvarez, V. G. Casabo, A. Ruiz-Garcia, and M. Bermejo. 2005. Kinetic modeling of the intestinal transport of sarafloxacin. Studies in situ in rat and in vitro in Caco-2 cells. J. Drug Target. 13:199-212.
Berquand, A., N. Fa, Y. F. Dufrene, and M. P. Mingeot-Leclercq. 2005. Interaction of the macrolide antibiotic azithromycin with lipid bilayers: effect on membrane organization, fluidity, and permeability. Pharm. Res. 22:465-475.
Siarheyeva, A., J. J. Lopez, and C. Glaubitz. 2006. Localization of multidrug transporter substrates within model membranes. Biochemistry. 45:6203-6211.
Hinrichs, J. W., K. Klappe, I. Hummel, and J. W. Kok. 2004. ATP-binding cassette transporters are enriched in non-caveolar detergent-insoluble glycosphingolipid-enriched membrane domains (DIGs) in human multidrug-resistant cancer cells. J. Biol. Chem. 279:5734-5738.
Hinrichs, J. W., K. Klappe, and J. W. Kok. 2005. Rafts as missing link between multidrug resistance and sphingolipid metabolism. J. Membr. Biol. 203:57-64.
Laurent, G., M. B. Carlier, B. Rollman, F. Van Hoof, and P. M. Tulkens. 1982. Mechanism of aminoglycoside-induced lysosomal phospholipidosis: in vitro and in vivo studies with gentamicin and amikacin. Biochem. Pharmacol. 31:3861-3870.
Ducarme, P., M. Rahman, and R. Brasseur. 1998. IMPALA: a simple restraint field to simulate the biological membrane in molecular structure studies. Proteins. 30:357-371.
Demel, R. A., W. S. Geurts van Kessel, R. F. Zwaal, B. Roelofsen, and L. L. van Deenen. 1975. Relation between various phospholipase actions on human red cell membranes and the interfacial phospholipid pressure in monolayers. Biochim. Biophys. Acta. 406:97-107.
Marsh, D. 1996. Lateral pressure in membranes. Biochim. Biophys. Acta. 1286:183-223.
Goormaghtigh, E., V. Raussens, and J. M. Ruysschaert. 1999. Attenuated total reflection infrared spectroscopy of proteins and lipids in biological membranes. Biochim. Biophys. Acta. 1422:105-185.
Tatulian, S. A. 2003. Attenuated total reflection Fourier transform infrared spectroscopy: a method of choice for studying membrane proteins and lipids. Biochemistry. 42:11898-11907.
Fringeli, U. P., and H. H. Gunthard. 1981. Infrared membrane spectroscopy. Mol. Biol. Biochem. Biophys. 31:270-332.
Fa, N., S. Ronkart, A. Schanck, M. Deleu, A. Gaigneaux, E. Goormaghtigh, and M. P. Mingeot-Leclercq. 2006. Effect of the antibiotic azithromycin on thermotropic behavior of DOPC or DPPC bilayers. Chem. Phys. Lipids. 144:108-116.
Komatsu, H., H. Saito, S. Okada, M. Tanaka, M. Egashira, and T. Handa. 2001. Effects of the acyl chain composition of phosphatidylcholines on the stability of freeze-dried small liposomes in the presence of maltose. Chem. Phys. Lipids. 113:29-39.
Hara, M., H. Yuan, Q. Yang, T. Hoshino, A. Yokoyama, and J. Miyake. 1999. Stabilization of liposomal membranes by thermozeaxanthins: carotenoid-glucoside esters. Biochim. Biophys. Acta. 1461:147-154.
Vie, V., N. Van Mau, E. Lesniewska, J. P. Goudonnet, F. Heitz, and C. Le Grimellec. 1998. Distribution of ganglioside G(M1) between two-component, two-phase phosphatidylcholine monolayers. Langmuir. 14:4574-4583.
Montero, M. T., J. Hernandez-Borrell, and K. M. W. Keough. 1998. Fluoroquinolone-biomembrane interactions: monolayer and calorimetric studies. Langmuir. 14:2451-2454.
Bechinger, B., J. M. Ruysschaert, and E. Goormaghtigh. 1999. Membrane helix orientation from linear dichroism of infrared attenuated total reflection spectra. Biophys. J. 76:552-563.
Ivanov, D., N. Dubreuil, V. Raussens, J. M. Ruysschaert, and E. Goormaghtigh. 2004. Evaluation of the ordering of membranes in multilayer stacks built on an ATR-FTIR germanium crystal with atomic force microscopy: the case of the H+,K+-ATPase-containing gastric tubulovesicle membranes. Biophys. J. 87:1307-1315.
Dalhoff, A., U. Petersen, and R. Endermann. 1996. In vitro activity of BAY 12-8039, a new 8-methoxyquinolone. Chemotherapy. 42:410-425.
Klopman, G., O. T. Macina, M. E. Levinson, and H. S. Rosenkranz. 1987. Computer automated structure evaluation of quinolone antibacterial agents. Antimicrob. Agents Chemother. 31:1831-1840.
Langlois, M. H., M. Montagut, J. P. Dubost, J. Grellet, and M. C. Saux. 2005. Protonation equilibrium and lipophilicity of moxifloxacin. J. Pharm. Biomed. Anal. 37:389-393.
Sun, J., S. Sakai, Y. Tauchi, Y. Deguchi, J. Chen, R. Zhang, and K. Morimoto. 2002. Determination of lipophilicity of two quinolone antibacterials, ciprofloxacin and grepafloxacin, in the protonation equilibrium. Eur. J. Pharm. Biopharm. 54:51-58.
Neves, P., A. Leite, M. Rangel, B. de Castro, and P. Gameiro. 2007. Influence of structural factors on the enhanced activity of moxifloxacin: a fluorescence and EPR spectroscopic study. Anal. Bioanal. Chem. 387:1543-1552.
Furet, Y. X., J. Deshusses, and J. C. Pechere. 1992. Transport of pefloxacin across the bacterial cytoplasmic membrane in quinolone-susceptible Staphylococcus aureus. Antimicrob. Agents Chemother. 36:2506-2511.
Hernandez-Borrell, J., and M. T. Montero. 2003. Does ciprofloxacin interact with neutral bilayers? An aspect related to its antimicrobial activity. Int. J. Pharm. 252:149-157.
Rodrigues, C., P. Gameiro, S. Reis, J. L. F. Lima, and B. de Castro. 2002. Interaction of grepafloxacin with large unilamellar liposomes: partition and fluorescence studies reveal the importance of charge interactions. Langmuir. 18:10231-10236.
Vazquez, J. L., M. T. Montero, S. Merino, O. Domenech, M. Berlanga, M. Vinas, and J. Hernandez-Borrell. 2001. Location and nature of the surface membrane binding site of ciprofloxacin: a fluorescence study. Langmuir. 17:1009-1014.
Pare, C., M. Lafleur, F. Liu, R. N. Lewis, and R. N. McElhaney. 2001. Differential scanning calorimetry and 2H nuclear magnetic resonance and Fourier transform infrared spectroscopy studies of the effects of transmembrane α-helical peptides on the organization of phosphatidylcholine bilayers. Biochim. Biophys. Acta. 1511:60-73.
Smaby, J. M., M. Momsen, V. S. Kulkarni, and R. E. Brown. 1996. Cholesterol-induced interfacial area condensations of galactosylceramides and sphingomyelins with identical acyl chains. Biochemistry. 35:5696-5704.
Smaby, J. M., M. M. Momsen, H. L. Brockman, and R. E. Brown. 1997. Phosphatidylcholine acyl unsaturation modulates the decrease in interfacial elasticity induced by cholesterol. Biophys. J. 73:1492-1505.
Bin, X., S. L. Horswell, and J. Lipkowski. 2005. Electrochemical and PM-IRRAS studies of the effect of cholesterol on the structure of a DMPC bilayer supported at an Au111 electrode surface, part 1: properties of the acyl chains. Biophys. J. 89:592-604.
Sun, J., S. Sakai, Y. Tauchi, Y. Deguchi, G. Cheng, J. Chen, and K. Morimoto. 2003. Protonation equilibrium and lipophilicity of olamufloxacin (HSR-903), a newly synthesized fluoroquinolone antibacterial. Eur. J. Pharm. Biopharm. 56:223-229.
Piddock, L. J., and Y. F. Jin. 1999. Antimicrobial activity and accumulation of moxifloxacin in quinolone-susceptible bacteria. J. Antimicrob. Chemother. 43:Suppl B:39-42.