Oritavancin diphosphate (LY333328 diphosphate) is a semisynthetic lipoglycopeptide analogue of vancomycin, inhibiting ArlS kinase activity with an IC50 value of 5.47µM [1]. Oritavancin can bind to the d-alanyl-d-alanine peptidoglycan termini of Lipid II, prevent the cross-linking of adjacent peptidoglycan chains, reduce the integrity of the cell wall, and cause membrane depolarization and increased permeability in intact Staphylococcus and Enterococcus[2]. Oritavancin has been widely used to kill drug-resistant Gram-positive bacteria and alleviate acute bacterial skin and soft tissue infections[3].
In vitro, Oritavancin (20μg/ml) treatment for 24 hours significantly promoted the production of reactive oxygen species (ROS) in J774 cells exposed to H2O2[4]. Treatment with 20mg/ml Oritavancin for 72 hours resulted in the accumulation of phospholipids, free cholesterol, and esterified cholesterol in rat embryonic fibroblasts[5].
In vivo, Oritavancin treatment via daily subcutaneous injection at a dose of 50mg/kg for 10 days significantly reduced the load of pulmonary Mycobacterium abscessus in the immunosuppressed mouse models[6]. Daily intravenous administration of 10mg/kg dose of Oritavancin for 2 days significantly reduced the concentration of penicillin-resistant Streptococcus pneumoniae in the meningitis rabbit model and decreased inflammatory indicators[7].
References:
[1] Bai J, Zhu X, Zhao K, et al. The role of ArlRS in regulating oxacillin susceptibility in methicillin-resistant Staphylococcus aureus indicates it is a potential target for antimicrobial resistance breakers[J]. Emerging microbes & infections, 2019, 8(1): 503-515.
[2] Brade K D, Rybak J M, Rybak M J. Oritavancin: a new lipoglycopeptide antibiotic in the treatment of gram-positive infections[J]. Infectious diseases and therapy, 2016, 5(1): 1-15.
[3] Saravolatz L D, Stein G E. Oritavancin: a long-half-life lipoglycopeptide[J]. Clinical Infectious Diseases, 2015, 61(4): 627-632.
[4] Lemaire S, Mingeot-Leclercq M P, Tulkens P M, et al. Study of macrophage functions in murine J774 cells and human activated THP-1 cells exposed to oritavancin, a lipoglycopeptide with high cellular accumulation[J]. Antimicrobial agents and chemotherapy, 2014, 58(4): 2059-2066.
[5] Van Bambeke F, Saffran J, Mingeot-Leclercq M P, et al. Mixed-lipid storage disorder induced in macrophages and fibroblasts by oritavancin (LY333328), a new glycopeptide antibiotic with exceptional cellular accumulation[J]. Antimicrobial agents and chemotherapy, 2005, 49(5): 1695-1700.
[6] Wang G, Tang J, Feng J, et al. Activity of oritavancin and its synergy with other antibiotics against Mycobacterium abscessus infection in vitro and in vivo[J]. International Journal of Molecular Sciences, 2021, 22(12): 6346.
[7] Cabellos C, Fernandez A, Maiques J M, et al. Experimental study of LY333328 (oritavancin), alone and in combination, in therapy of cephalosporin-resistant pneumococcal meningitis[J]. Antimicrobial agents and chemotherapy, 2003, 47(6): 1907-1911.
Oritavancin diphosphate (LY333328 diphosphate)是一种半合成脂糖肽类万古霉素类似物，可抑制ArlS激酶活性，IC50值为5.47μM[1]。Oritavancin能与脂质II的d-alanyl-d-alanine肽聚糖末端结合，阻止相邻肽聚糖链的交联，降低细胞壁完整性，并在完整的葡萄球菌和肠球菌中引起膜去极化和通透性增加[2]。Oritavancin已被广泛用于杀灭耐药革兰氏阳性菌，并缓解急性细菌性皮肤和皮肤软组织感染[3]。
在体外，使用20µg/ml的Oritavancin处理暴露于H2O2的J774细胞24小时，显著促进了细胞内活性氧（ROS）的产生[4]。使用20mg/ml的Oritavancin处理大鼠胚胎成纤维细胞72小时，导致磷脂、游离胆固醇和酯化胆固醇的积累[5]。
在体内，每日皮下注射50mg/kg剂量的Oritavancin，持续10天，显著降低了免疫抑制小鼠模型中的肺Mycobacterium abscessus的细菌载量[6]。每日静脉注射10mg/kg剂量的Oritavancin，连续2天，显著降低了脑膜炎兔模型中青霉素耐药肺炎链球菌的浓度，并减少了炎症指标[7]。