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Probing drug/lipid interactions at the molecular level represents an important challenge …


Biology Articles » Biophysics » Molecular Biophysics » Characterization of the Interactions between Fluoroquinolone Antibiotics and Lipids: a Multitechnique Approach » Introduction

Introduction
- Characterization of the Interactions between Fluoroquinolone Antibiotics and Lipids: a Multitechnique Approach

Since their discovery in the early 1960s, the quinolone groupof antibacterials has generated considerable clinical and scientificinterest including the development of the second-generationquinolones like ciprofloxacin. These wide spectrum drugs arecharacterized by the introduction of fluor into position C-6on the molecule. Progressive modifications in their chemicalstructure have resulted in improved breadth and potency of invitro activity and pharmacokinetics (1Go). The most significantdevelopments have been enhancement of the therapeutic potentialof fluoroquinolones thanks to liposomal encapsulation (2Go–4Go)and improved anti-Gram-positive activity of the newer compoundslike moxifloxacin (5Go).

Due to their ability to accumulate inside phagocytes (1Go,6Go–8Go),fluoroquinolones are also useful for eliminating facultativeintracellular pathogens that resist phagocytic death. We recentlyshowed that fluoroquinolones accumulate in macrophages and showactivity against a large array of intracellular organisms includingListeria monocytogenes and Staphylococcus aureus (9Go). Quitesignificant differences among closely related derivatives havebeen observed with the following ranking in cellular accumulationand intracellular activity: ciprofloxacin < levofloxacin< garenoxacin < moxifloxacin (9Go). So far, to our knowledge,this has not received satisfactory explanation.

Characterization of fluoroquinolones uptake by eukaryotic cellssuggested that both passive diffusion and active transport systemsare involved. The transbilayer diffusion of fluoroquinoloneshas been demonstrated (10Go) and our group reported that ciprofloxacin,but not moxifloxacin, is subject to constitutive efflux in J774macrophages through the activity of an MRP-related transporter(11Go).

Drug/lipid interactions can modulate not only translocationof the drug through the natural membranes but also its interactionwith efflux proteins (12Go,13Go). In this respect, it is well knownthat 1), substrates have to be transported from the lipid bilayerto the transporter protein before a capture mechanism of thedrug by the inner leaflet of the cytoplasmic membrane (14Go);and 2), the activity of transporter is critically dependenton the surrounding lipid bilayer environment (15Go,16Go), whichmay be modified by drugs.

In view of the critical role of lipids for the drug cellularuptake and differences observed for two closely related compounds,ciprofloxacin and moxifloxacin (Fig. 1), we investigated theinteractions of these two fluoroquinolones with lipids, usingan array of complementary techniques. For both ciprofloxacinand moxifloxacin, atomic force microscopy (AFM) reveals an erosionof dipalmitoylphosphatidylcholine (DPPC) domains within dioleoylphosphatidylcholine(DOPC) fluid phase while Langmuir studies show a condensingeffect. Further molecular studies show that fluoroquinolonescan 1), exchange from lipids to aqueous phases (phase transferand molecular modeling studies); 2), decrease the all-transconformation of lipid acyl chain (attenuated total reflectionFourier transform Infra-Red (ATR-FTIR)); and 3), increase thelipid disorder (ATR-FTIR). When the effects of the two fluoroquinolonesare compared, it clearly appears that moxifloxacin has a highercondensing effect related to a lower propensity to be releasedin the aqueous phase from lipid monolayer and to a higher abilityto decrease the all-trans conformation of lipid acyl chain withoutmarked effect in lipid-chain orientation. All together, differencesof ciprofloxacin as compared to moxifloxacin in their interactionswith lipids can be related to differences in their cellularaccumulation and therefore activity against intracellular bacteria.


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