title: Structure-activity studies on polymyxin derivatives carrying three positive charges only reveal a new class of compounds with strong antibacterial activity.
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.
authors.affiliation: Northern 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. Electronic address: martti.vaara@northernantibiotics.com.
authors.forename: Martti
authors.initials: M
authors.lastname: Vaara
authors.affiliation: Northern Antibiotics Ltd., FI-02150 Espoo, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Vaara
authors.affiliation: Department of Medical Microbiology & Infectious Disease, Institute of Infection & Immunity, UGW Main Building, Heath Park Campus, Cardiff, Wales, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Tyrrell
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000652:urine; D001419:Bacteria / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects; D008252:Macaca fascicularis; D011113:Polymyxins / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000652:urine; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; C546019:NAB 739 peptide; D011113:Polymyxins; C121746:polymyxin B(1)
keywords: Acinetobacter baumannii; Escherichia coli; Excretion to urine; HK-2; Klebsiella pneumoniae; NAB739, NAB815; Nephrotoxicity; Pseudomonas aeruginosa