Gallardo-Godoy Alejandra, Muldoon Craig, Becker Bernd, Elliott Alysha G, Lash Lawrence H, Huang Johnny X, Butler Mark S, Pelingon Ruby, Kavanagh Angela M, Ramu Soumya, Phetsang Wanida, Blaskovich Mark A T, Cooper Matthew A
Institute for Molecular Bioscience, The University of Queensland , Brisbane, Queensland 4072, Australia.
Department of Pharmacology, School of Medicine, Wayne State University , 540 East Canfield Avenue, Detroit, Michigan 48201, United States.
J Med Chem. 2016 Feb 11;59(3):1068-77. doi: 10.1021/acs.jmedchem.5b01593. Epub 2016 Jan 27.
The polymyxin lipodecapeptides colistin and polymyxin B have become last resort therapies for infections caused by highly drug-resistant Gram-negative bacteria. Unfortunately, their utility is compromised by significant nephrotoxicity and polymyxin-resistant bacterial strains. We have conducted a systematic activity-toxicity investigation by varying eight of the nine polymyxin amino acid free side chains, preparing over 30 analogues using a novel solid-phase synthetic route. Compounds were tested against a panel of Gram-negative bacteria and counter-screened for in vitro cell toxicity. Promising compounds underwent additional testing against primary kidney cells isolated from human kidneys to better predict their nephrotoxic potential. Many of the new compounds possessed equal or better antimicrobial potency compared to polymyxin B, and some were less toxic than polymyxin B and colistin against mammalian HepG2 cells and human primary kidney cells. These initial structure-activity and structure-toxicity studies set the stage for further improvements to the polymyxin class of antibiotics.
多粘菌素脂十肽类药物粘菌素和多粘菌素B已成为治疗由高度耐药革兰氏阴性菌引起的感染的最后手段。不幸的是，它们的效用因严重的肾毒性和耐多粘菌素菌株而受到损害。我们通过改变九种多粘菌素游离氨基酸侧链中的八种，采用一种新颖的固相合成路线制备了30多种类似物，进行了系统的活性-毒性研究。化合物针对一组革兰氏阴性菌进行了测试，并针对体外细胞毒性进行了反向筛选。有前景的化合物对从人肾分离的原代肾细胞进行了额外测试，以更好地预测它们的肾毒性潜力。与多粘菌素B相比，许多新化合物具有同等或更好的抗菌效力，并且一些对哺乳动物HepG2细胞和人原代肾细胞的毒性比多粘菌素B和粘菌素小。这些初步的构效关系和构毒关系研究为进一步改进多粘菌素类抗生素奠定了基础。
