Vaara, MarttiVaara, TimoTyrrell, Jonathan M.2018-07-112025-08-272017-05Vaara, M, Vaara, T & Tyrrell, J M 2017, 'Structure-activity studies on polymyxin derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity', Peptides, vol. 91, pp. 8-12. https://doi.org/10.1016/j.peptides.2017.03.002http://hdl.handle.net/10138/237084Recent years have brought in an increased interest to develop improved polymyxins. The currently used polymyxins, i.e. polymyxin B and colistin (polymyxin E) are pentacationic lipopeptides that possess a cyclic heptapeptide part with three positive charges, a linear "panhandle" part with two positive charges, and a fatty acyl tail. Unfortunately, their clinical use is shadowed by their notable nephrotoxicity. We have previously developed a polymyxin derivative NAB739 which lacks the positive charges in the linear part. This derivative is better tolerated than polymyxin B in cynomolgus monkeys and is, in contrast to polymyxin B, excreted into urine in monkeys and rats. Here we have conducted further structure-activity relationship (SAR) studies on 17 derivatives with three positive charges only. We discovered a remarkably antibacterial class, as exemplified by NAB815, that carries two positive charges only in the cyclic part. (C) 2017 Elsevier Inc. All rights reserved.5enginfo:eu-repo/semantics/openAccessNAB739, NAB815Escherichia coliKlebsiella pneumoniaeAcinetobacter baumanniiPseudomonas aeruginosaExcretion to urineNephrotoxicityHK-2BiomedicineBiochemistry, cell and molecular biologyPharmacyArticleopenAccess59129476-349f-44ba-9159-958eca58f8f885015381786000402444400002