Effect of magnesium complexation by fluoroquinolones on their antibacterial properties

Abstract

By using infrared and 19F nuclear magnetic resonance spectroscopies, we localized the binding site and measured the affinity of magnesium for six fluoroquinolones. It was proven that magnesium is situated between the ketone and the carboxylate groups. We determined the binding constants for the 1:1 Mg2e-drug complex in solution. Sparfloxacin and pefloxacin, with affinity constants (K.) of (10.1 + 0.6) x 102 M1 and (21 1) x 102 M-', respectively, were the least and the most bound, respectively. The trend of the affinities of the assayed fluoroquinolones for magnesium was correlated with their antimicrobial activities against four bacteria and with their accumulation by these bacteria. The reference strain, Escherichia coli KL16, and two resistant mutants, NalA (gyrase mutation) and NalB (uptake defect), plus Staphylococcus aureus 209P were used. It appeared that, in every case, an impairment of accumulation is responsible for the increase in the MICs observed upon the addition of magnesium.The advantages of fluoroquinolone antibiotics include their excellent activity against various bacteria, a low frequency of adverse effects, and good absorption on oral administration. However, different studies (5,11,14,22) have shown that some cations, such as magnesium and aluminum, cause malabsorption of most fluoroquinolones, which may result in therapeutic failure. Moreover, the MIC of an antibacterial agent is the result of two steps: the entry of the molecule into the bacterial cell and its interaction with its target within the cell. The rate of penetration of fluoroquinolones across the bacterial cell envelope depends on various physical properties of the drug (6,12,18,20), with its hydrophobicity (3) and the presence of magnesium (7, 13) being major factors. While conflicting reports have been accumulating in the literature on the way in which quinolone antibacterial agents inhibit DNA gyrasecatalyzed supercoiling (17,24,25,32,34), magnesium is also implicated in the binding of the drug to DNA (17,21,33). To better understand the role of magnesium in these various features of quinolone activity, we aimed to determine the site of the binding and to measure the affinity of this ion for some fluoroquinolones. Our approach includes infrared (IR) and '9F nuclear magnetic resonance (NMR) spectroscopies, which have never been used for this purpose, and a comparative study of the effect of magnesium concentration on the in vitro activities of the assayed fluoroquinolones and on their uptake by four bacterial strains.( IR spectra. The solutions of pefloxacin (1 mM) and sparfloxacin (5 mM) were prepared from 10 mM stock solutions either in 100% D20 or in buffered D20 propanesulfonic acid (MOPS), 20 mM KCl) at pD 7.4. Because the spectra were differential spectra (the buffer was subtracted), their qualities may vary with the compound, and in order to ensure better-quality spectra, the concentration of sparfloxacin had to be increased to 5 mM. The pH meter reading was adjusted by DCl or KOD at 0.4 unit less than the required val...

Comparison of Antibacterial Activity of Fluoroquinolones with Their Sucralfate-complexes against Clinically-isolated Bacteria

“…Some reports said that the concomitant use of fluoroquinolones and cation-containing drugs caused the reduction of antibacterial activity, [9][10][11] and others were not. 12) Therefore, to clarify the degree for the decrease of antibacterial activity of fluoroquinolones by aluminum-containing antacid, we conducted the growth-inhibitory experiments of ten fluoroquinolone against E. coli strain ATCC25922 in MHB in the presence or absence of sucralfate (Table 1).…”

“…However, reported antibiotic activity of various fluoroquinolones with metal complexes is controversial. Some described that the reduction of antibacterial activity was observed, [9][10][11] and others were not. 12) Therefore, to provide a uniform criterion for commingling usage of fluoroquinolones with sucralfate, we attempted a comparison of antibacterial activity of fluoroquinolones with their sucralfatecomplexes against clinically-isolated bacteria by in vitro study.…”

New rhenium complexes with ciprofloxacin as useful models for understanding the properties of [99mTc]-ciprofloxacin radiopharmaceutical

“…Particularly, if we take into account that the atoms that probably interact with the metal (4-oxo carbonyl and carboxylate oxygen atoms) are the same that have been proposed to interact with DNA gyrase. 7,9 In contrast to this view, other authors have proposed that metal atoms can be involved in the interaction between ciprofloxacin and DNA-gyrase , 7,[18][19][20] which could A c c e p t e d m a n u s c r i p t 29 Zr, 29 Mo, 24 Ag, 30 Cd, 21,26 Pt, 31 U 32 and Eu 33 have been reported, and there is even a review of these metal complexes. 19 As mentioned above, the most common coordination mode of ciprofloxacin is through the oxygen atoms of the 4-oxo carbonyl and the carboxylate groups, forming a chelating ring of six atoms.…”

Immunohistochemistry of Articular Cartilage from Immature Beagle Dogs Dosed with Difloxacin

“…Quinolones are potent chelating agents (16,17,20) and there is emerging evidence that they damage juvenile joint cartilage of animals due to their chelating properties, in particular by forming stable chelate complexes with magnesium (24,27). In this respect, it is of interest that lameness and gait alterations closely resembling quinolone-induced arthropathy were described in magnesiumdeficient dogs almost 4 decades ago (26).…”