Structure-activity studies on polymyxin derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity

Martti Vaara, Timo Vaara, Jonathan M Tyrrell

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Recent 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.

Original languageEnglish
Pages (from-to)8-12
Number of pages5
JournalPeptides
Volume91
DOIs
Publication statusPublished - May 2017

Bibliographical note

Copyright © 2017 Elsevier Inc. All rights reserved.

Keywords

  • Animals
  • Anti-Bacterial Agents/chemistry
  • Bacteria/drug effects
  • Cell Line
  • Dose-Response Relationship, Drug
  • Kidney/drug effects
  • Macaca fascicularis
  • Polymyxins/analogs & derivatives
  • Rats
  • Structure-Activity Relationship

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