Solubilization of Pyrimethamine, Antibacterial Drug, by Low-Molecular-Weight Succinoglycan Dimers Isolated from Shinorhizobium meliloti

Abstract

The use of pyrimethamine as antibacterial drug is limited by the poor solubility. To enhance its solubility, we prepared complexes of pyrimethamine with low-molecular-weight succinoglycan isolated from Sinorhizobium meliloti. Low-molecular-weight succinoglycans are monomers, dimers, and trimers of the succinoglycan repeating unit. The monomers and dimers were separated into their three species (M1, M2, and M3) and four fractions (D1 to D4) using chromatographic techniques, which were shown to be nontoxic. The solubility of pyrimethamine was markedly increased up to 42 fold by succinoglycan D3, where the level of its solubility enhancement was even 8-20 fold higher comparing with cyclodextrin or its derivatives. The complex formation of succinoglycan D3 with pyrimethamine was confirmed by 1 H nuclear magnetic resonance spectroscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, and molecular modeling studies. Herein, we suggest that the low-molecular-weight succinoglycans may be utilized as highly effective solubilizers of pyrimethamine for pharmaceutical purposes.

Carbohydrate-Based Host-Guest Complexation of Hydrophobic Antibiotics for the Enhancement of Antibacterial Activity

“…Polysaccharides are generally natural polymers such as chitosan, alginate, cellulose, and agar and are used in established drug delivery systems [ 105 , 106 ]. In recent studies, linear oligosaccharides have also been used in drug delivery systems for host-guest complexation [ 23 , 33 ]. In this section, we summarize the study of linear oligosaccharide complexes with antibiotics and flavonoids ( Figure 6 ).…”

“…Succinoglycan (SG) dimers can complex with pyrimethamine to form an antibacterial drug [ 33 ]. Pyrimethamine inhibits dihydrofolate reductase (DHFR), which is an enzyme essential for the conversion of folic acid into folinic acid during nucleic acid biosynthesis in protozoa.…”

“…Linear oligosaccharides can provide amphiphilicity because of their hydrophilic and hydrophobic surfaces on sugar backbones, and solubilize lipophilic compounds in water [ 32 , 33 , 34 ]. Sinorhizobium meliloti produces low-molecular-weight (LMW) succinoglycans (SCs) which are monomers, dimers, and trimers of the octasaccharide repeating unit [ 35 ].…”

Supramolecular Complexation of Carbohydrates for the Bioavailability Enhancement of Poorly Soluble Drugs

“…From this point of view, the hydrophobic character of linear carbohydrates was investigated with fluorescence probes, and the host-guest complexation might involve an induced-fit type adjustment [69]. Non-cyclic hexadecasaccharide has been reported as an effective complexing agent for pyrimethamine, haloperidol, or isoflavonoids (Figure 1h) [70,71,72]. In fact, the solubility of the antimalarial drug pyrimethamine and antipsychotic medication haloperidol was increased 42- and 87-fold in water by complexing with succinoglycan dimer D3 [70,71].…”

“…Non-cyclic hexadecasaccharide has been reported as an effective complexing agent for pyrimethamine, haloperidol, or isoflavonoids (Figure 1h) [70,71,72]. In fact, the solubility of the antimalarial drug pyrimethamine and antipsychotic medication haloperidol was increased 42- and 87-fold in water by complexing with succinoglycan dimer D3 [70,71]. Even in octasaccharides, a solubility enhancement of pindolol was described, and their cytotoxic effect was low enough to warrant further study [73].…”