Glycosides of Nadifloxacin-Synthesis and Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus.

The increase in the number of bacteria that are resistant to multiple antibiotics poses a serious clinical problem that threatens the health of humans worldwide. Nadifloxacin (1) is a highly potent antibacterial agent with broad-spectrum activity. However, its poor aqueous solubility has limited its use to topical applications. To increase its solubility, it was glycosylated herein to form a range of trans-linked (3a-e) and cis-linked (7a,b) glycosides, each of which was prepared and purified to afford single anomers. The seven glycoside derivatives (3a-e, 7a,b) were examined for potency against eight strains of S. aureus, four of which were methicillin-resistant. Although less potent than free nadifloxacin (1), the α-L-arabinofuransoside (3a) was effective against all strains that were tested (minimum inhibitory concentrations of 1-8 µg/mL compared to 0.1-0.25 µg/mL for nadifloxacin), demonstrating the potential of this glycoside as an antibacterial agent. Estimation of Log P as well as observations made during preparation of these compounds reveal that the solubilities of the glycosides were greatly improved compared with nadifloxacin (1), raising the prospect of its use in oral applications.

Synthesis and biological analysis of novel glycoside derivatives of l-AEP, as targeted antibacterial agents.

To develop targeted methods for treating bacterial infections, the feasibility of using glycoside derivatives of the antibacterial compound l-R-aminoethylphosphonic acid (l-AEP) has been investigated. These derivatives are hypothesized to be taken up by bacterial cells via carbohydrate uptake mechanisms, and then hydrolyzed in situ by bacterial borne glycosidase enzymes, to selectively afford l-AEP. Therefore the synthesis and analysis of ten glycoside derivatives of l-AEP, for selective targeting of specific bacteria, is reported. The ability of these derivatives to inhibit the growth of a panel of Gram-negative bacteria in two different media is discussed. ß-Glycosides (12a) and (12b) that contained l-AEP linked to glucose or galactose via a carbamate linkage inhibited growth of a range of organisms with the best MICs being <0.75mg/ml; for most species the inhibition was closely related to the hydrolysis of the equivalent chromogenic glycosides. This suggests that for (12a) and (12b), release of l-AEP was indeed dependent upon the presence of the respective glycosidase enzyme.

Synthesis and antibacterial profiles of targeted triclosan derivatives.

There is an ongoing urgent need for new targeted antibacterial compounds with novel mechanisms of action for the treatment of infections caused by bacteria that are resistant to currently available materials. Since the expression of glycosidase enzymes within bacteria is unequally distributed, glycoside derivatives of antibacterial agents offer potential as targeted prodrugs for bacterial infections. Herein we report the synthesis and characterisation of four α-D-glycopyranosides and three ß-D-glycopyranosides of the broad antibacterial agent triclosan, in generally good synthetic yields, and with excellent purities. Each glycoside was analysed to determine its ability to inhibit the growth of a wide range of Gram-negative and Gram-positive organisms, including many of clinical significance. All of the triclosan glycosides that were synthesized demonstrated antibacterial activity against many of the organisms that were examined. For example, ß-galactoside (3a) and α-arabinoside (3c) had MIC values of 0.5 µg/ml for several strains of S. aureus and S. haemolyticus. The triclosan glycosides were also generally found to be more water soluble and much more selective than the underivatized triclosan, making them ideal both for the targeted inhibition of bacterial growth and as agents for the selective recovery of bacteria from mixed cultures. In the latter case, two Bacillus strains could be identified from various strains of Bacillus and Staphylococcus after inoculation onto Nutrient Agar No. 2 with 0.25 µg/ml triclosan-α-D-glucopyranoside (3e). This glucoside may, therefore, be of use for the isolation and identification of the food-poisoning organism Bacillus cereus.