title: Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents.
abstract: The lack of novel antibiotics against gram-negative bacteria has reinstated polymyxins as the drugs of last resort to treat serious infections caused by extremely multiresistant gram-negative organisms. However, polymyxins are nephrotoxic, and this feature may complicate therapy or even require its discontinuation. Like that of aminoglycosides, the nephrotoxicity of polymyxins might be related to the highly cationic nature of the molecule. Colistin and polymyxin B carry five positive charges. Here we show that novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents. NAB739 has a cyclic peptide portion identical to that of polymyxin B, but in the linear portion of the peptide, it carries the threonyl-D-serinyl residue (no cationic charges) instead of the diaminobutyryl-threonyl-diaminobutyryl residue (two cationic charges). The MICs of NAB739 for 17 strains of Escherichia coli were identical, or very close, to those of polymyxin B. Furthermore, NAB739 was effective against other polymyxin-susceptible strains of Enterobacteriaceae and against Acinetobacter baumannii. At subinhibitory concentrations, it dramatically sensitized A. baumannii to low concentrations of antibiotics such as rifampin, clarithromycin, vancomycin, fusidic acid, and meropenem. NAB739 methanesulfonate was a prodrug analogous to colistin methanesulfonate. NAB740 was the most active derivative against Pseudomonas aeruginosa. NAB7061 (linear portion of the peptide, threonyl-aminobutyryl) lacked direct antibacterial activity but sensitized the targets to hydrophobic antibiotics by factors up to 2,000. The affinities of the NAB compounds for isolated rat kidney brush border membrane were significantly lower than that of polymyxin B.
authors.affiliation: Northern Antibiotics Ltd, Helsinki, Finland. martti.vaara@northernantibiotics.com
authors.forename: Martti
authors.initials: M
authors.lastname: Vaara
authors.forename: John
authors.initials: J
authors.lastname: Fox
authors.forename: Günther
authors.initials: G
authors.lastname: Loidl
authors.forename: Osmo
authors.initials: O
authors.lastname: Siikanen
authors.forename: Juha
authors.initials: J
authors.lastname: Apajalahti
authors.forename: Frank
authors.initials: F
authors.lastname: Hansen
authors.forename: Niels
authors.initials: N
authors.lastname: Frimodt-Møller
authors.forename: Junya
authors.initials: J
authors.lastname: Nagai
authors.forename: Mikihisa
authors.initials: M
authors.lastname: Takano
authors.forename: Timo
authors.initials: T
authors.lastname: Vaara
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006224:Cricetinae; D005347:Fibroblasts / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000145:classification / Q000187:drug effects*; D007672:Kidney Cortex; D008168:Lung / Q000166:cytology / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008871:Microvilli / Q000378:metabolism; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011112:Polymyxin B