Roberts Kade D, Azad Mohammad A K, Wang Jiping, Horne Andrew S, Thompson Philip E, Nation Roger L, Velkov Tony, Li Jian
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia; Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville 3052, Victoria, Australia.
ACS Infect Dis. 2015 Nov 13;1(11):568-575. doi: 10.1021/acsinfecdis.5b00085. Epub 2015 Sep 4.
Polymyxin B and colistin are currently used as a 'last-line' treatment for multidrug-resistant Gram-negative bacteria. However very little is known about the pharmacological differences between polymyxin B, polymyxin B, colistin A, colistin B, the major cyclic lipopeptides components present in polymyxin B and colistin products. Here, we report on the and antimicrobial activity and toxicity of these major lipopeptide components. All four lipopeptides had comparable MICs (<0.125-4 mg/L) against a panel of clinical Gram-negative isolates. They also had comparable antimicrobial activity (Δlog CFU/mL >-3) and nephrotoxicity (mild to moderate histological damage) in mouse models. However, polymyxin B and colistin A showed significantly higher (> 3-fold) apoptotic effect on human kidney proximal tubular HK-2 cells than polymyxin B2 and colistin B, respectively. Compared to the commercial polymyxin and colistin products, the individual lipopeptide components had slightly more antimicrobial activity. Our results highlight the need to re-assess pharmacopoeial standards for polymyxins B and colistin and to standardize the composition of the different commercial products of polymyxin antibiotics.
多粘菌素B和黏菌素目前被用作多重耐药革兰氏阴性菌的“最后一线”治疗药物。然而，对于多粘菌素B、多粘菌素B、黏菌素A、黏菌素B（多粘菌素B和黏菌素产品中存在的主要环脂肽成分）之间的药理学差异知之甚少。在此，我们报告这些主要脂肽成分的抗菌活性和毒性。所有四种脂肽对一组临床革兰氏阴性分离株的最低抑菌浓度（MICs）相当（<0.125 - 4毫克/升）。在小鼠模型中，它们还具有相当的抗菌活性（Δlog CFU/毫升 > -3）和肾毒性（轻度至中度组织学损伤）。然而，多粘菌素B和黏菌素A对人肾近端小管HK - 2细胞的凋亡作用分别比多粘菌素B2和黏菌素B显著更高（>3倍）。与市售的多粘菌素和黏菌素产品相比，单个脂肽成分具有稍高的抗菌活性。我们的结果强调需要重新评估多粘菌素B和黏菌素的药典标准，并规范多粘菌素抗生素不同商业产品的成分。
