Structure-activity studies on polymyxin derivatives carrying three positive charges only reveal a new class of
Martti Vaara1, Timo Vaara2, Jonathan M Tyrrell3
1Northern Antibiotics Ltd., FI-02150 Espoo, Finland; Division of Clinical Microbiology, Helsinki University Hospital, FI-00029 Helsinki, Finland; Department of Bacteriology and Immunology, Helsinki University Medical School, FI-00014 Helsinki, Finland.
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.
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