In vitro effects of novel glycopeptide antibiotics on the reactivity of the lipopolysaccharide (LPS) of S. minnesota R595.

Four novel glycopeptide antibiotics, namely MDL 62708, MDL 63155, MDL 62827, MDL 62873 (mideplanin), plus teicoplanin, which differ in their chemical structure, were used to examine the relationship between the structure of glycopeptides and their LPS neutralization activity. Compound MDL 62708 (100 micrograms/ml) significantly reduced (P < 0.01 vs. antibiotic-free LPS, by Fisher's PLSD Test) metachromatic reactivity of S. minnesota R595 LPS (500 micrograms/ml) as evaluated by the DMB test. The remaining glycopeptides showed a significant reduction of the metachromatic reactivity, although at concentrations (333 and 1000 micrograms/ml) higher than MDL 62708. Data obtained with LAL test appeared in accordance with those of the other techniques: all the glycopeptides used (100 and 1000 micrograms/ml) significantly (P < 0.05) reduced the reactivity of S. minnesota R595 LPS (50 pg/ml), and the lowest concentration of MDL 62708 (10 pg/ml) used produced a substantial, although not significant, reduction of the LPS reactivity with LAL. The antibiotic/LPS ratios associated to a significant reduction of LPS reactivity were 3.3/5 (wt/wt) and 2/1 (wt/wt) for DMB and LAL tests respectively. Such ratio appeared to be even lower for MDL 62708. In conclusion, the four new glycopeptides, when tested at an antibiotic/LPS ratio about 1000 times lower than that which can be found in vivo, were able to reduce the reactivity of LPS in the in vitro models used. Teicoplanin aglycone MDL 62708, which also lacks the teicoplanin fatty acid, seems to have the same anti-LPS activity as the parental antibiotic, thus suggesting an important role for the glycopeptide backbone and NH2 groups in LPS-neutralizing effect.