The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited latestage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K ؉ . The timing of these changes correlated with rapid, concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.The emergence and spread of bacterial resistance to vancomycin, an important antibiotic used to treat serious infections caused by gram-positive bacteria, has prompted active research to discover new glycopeptides and semisynthetic analogs with improved antimicrobial properties. Vancomycin and related glycopeptide antibiotics inhibit cell wall synthesis in susceptible bacteria by binding with high specificity to peptidoglycan precursors containing the C-terminal D-alanyl-D-alanine (D-Ala-DAla) motif (8). The peptide portion of glycopeptide antibiotics forms a carboxylate binding pocket that imparts, through a combination of five hydrogen bonds plus favorable hydrophobic interactions, strong affinity for the D-Ala-D-Ala-containing terminus of lipid II (8,46,54). Rational approaches toward the design of glycopeptides with improved antimicrobial activities have been described previously (for reviews, see references 35 and 36). One promising approach has been the discovery of lipoglycopeptides, analogs containing hydrophobic groups substituted at the amine position of the disaccharide moiety (20,39,40,45).Telavancin, a semisynthetic derivative of vancomycin possessing a hydrophobic (decylaminoethyl) side chain appended to the vancosamine sugar and a hydrophilic [(phosphonomethyl)aminomethyl] group on the resorcinol-like 4Ј position of amino acid 7 (33), is in late-stage clinical development for the treatment of serious gram-positive infections. Telavancin and other lipoglycopeptides exhibit superior in vitro activity compa...

Danggui Buxue Tang (DBT), a Chinese medicinal decoction that is commonly used as a dietary supplement in treating woman with menopausal irregularity, contains two herbs: Radix Astragali (Huangqi) and Radix Angelicae Sinensis (Danggui). The ratio of Radix Astragali and Radix Angelicae Sinensis used in DBT should be 5:1 as described in China in 1247 A.D.; however, the rationale of this formula has not been given. Here, the chemical and biological properties of DBT, prepared from different ratios of the drugs, were determined. Significantly, higher amounts of Radix Astragali-derived astragaloside IV, calycosin, and formononetin and Radix Angelicae Sinensis-derived ferulic acid were found in DBT with Radix Astragali and Radix Angelicae Sinensis in a 5:1 ratio. By using the biological effects of DBT in stimulating osteoblast proliferation, estrogen promoter activation, and anti-platelet aggregation activity, the drug ratio of 5:1 produced the best effects. In addition, the use of ethanol-treated Radix Angelicae Sinensis enhanced the efficacy of DBT, and the treatment further increased the solubilities of chemical constituents. By analyzing the correlation of chemical and biological results, several chemicals showed positive correlation with DBT-induced bioactivities. The current results support the ancient formulation of DBT, and the identified chemicals could serve as markers for quality control of DBT.

Despite the classical hormonal effect, estrogen possesses a neuroprotective effect in the brain, which has led many to search for novel treatments for neurodegenerative diseases. Flavonoids, a group of compounds mainly derived from vegetables, share a resemblance, chemically, to estrogen, and indeed, some have been used as estrogen substitutes. To search for potential therapeutic agents against neurodegenerative diseases, different subclasses of flavonoids were analyzed and compared with estrogen. First, the estrogenic activities of these flavonoids were determined by activating the estrogen-responsive elements in cultured MCF-7 breast cancer cells. Second, the neuroprotective effects of flavonoids were revealed by measuring its inhibition effects on the formation of reactive oxygen species, the aggregation of beta-amyloid, and the induction of cell death by beta-amyloid in cultured neuronal PC12 cells. Among these flavonoids, baicalein, scutellarin, hibifolin, and quercetin-3'-glucoside possessed the strongest effect in neuroprotection; however, the neuroprotective activity did not directly correlate with the estrogenic activity of the flavonoids. Identification of these flavonoids could be very useful in finding potential drugs, or food supplements, for treating Alzheimer's disease.