Oritavancin (diphosphate)

Oritavancin diphosphate (LY333328 diphosphate), a semisynthetic derivative of Vancomycin (HY-B0671), is an orally active glycopeptide antibiotic with bactericidal activity against gram-positive organisms. Oritavancin diphosphate shows antibacterial effect against B. anthracis, such as Ames strain with a MIC value of 0.015 g/mL. Oritavancin diphosphate inhibits cell wall synthesis and disrupts the membrane potential. Oritavancin diphosphate inhibits ArlS kinase activity thereby interfering the signal transduction. Oritavancin diphosphate enters cells by adsorptive endocytosis, which drives it to lysosomes, where it exerts antibiotic activity^{[1][2][3][4][5]}. In Vitro: Oritavancin diphosphate (25 μM, 30 min) dose-dependently inhibits the kinase activity of ArlS (3 μg) by 98% with an IC⁵⁰ value of 5.47 μΜ in vitro^[1].
Oritavancin diphosphate (0.7 μM, 42 h) decreases spx expression in the USA300-Pspx strain^[1].
Oritavancin diphosphate (3.1 μM, 24 h) disrupts mature MRSA biofilms and facilitates bactericidal activity of oritavancin diphosphate and Oxacillin (HY-B0925A) against embedded S. aureus cells^[1].
Oritavancin diphosphate’ (0-80 μg/mL, 2 h) incubation with increasing extracellular concentrations and the uptake by cells proceed in a cooperative manner in J774 macrophages^[2].
Oritavancin diphosphate (25 mg/L, 24 h) exerts a marked bactericidal effect against intracellular S. aureus^[2].

Oritavancin diphosphate accumulation by different cell types^[2]

(The cells were incubated for 2 h at 37°C with 25 mg of the drug per liter in a medium containing 10% FCS)^[2]

Cell type	Accumulation ratio (no. of determinations)
J774 mouse macrophages	66.4±11.8 (12)
THP-1 human monocytes	84.3±7.0 (9)
Rat embryo fibroblasts	72.4±9.4 (6)
LLC-PK1 pig kidney proximal tubular cells	37.8±6.4 (3)
Caco-2 human colorectal cells.	13.8±0.4 (3)

In Vivo: Oritavancin diphosphate (i.p. for 1 and 3 mg/kg or i.v. for 15 and 50 mg/kg, every 48 h for 14 days or a single dose for 30 days) provides significant protection in the mouse inhalation anthrax model^[3].