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Antimicrob. Agents Chemother. doi:10.1128/AAC.00405-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents

Northern Antibiotics Ltd. FI-00720 Helsinki, and Division of Clinical Microbiology, Helsinki University Hospital, FI-00029 HUSLAB, Helsinki, and Alimetrics Ltd, FI-02920 Espoo, Finland; Alta Bioscience, University of Birmingham, Birmingham B15 2TT, UK; Bachem AG, CH-4416 Bubendorf, Switzerland; Statens Serum Institut, Copenhagen S, DK-2300, Denmark; and Hiroshima University, Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan

^* To whom correspondence should be addressed. Email: martti.vaara{at}northernantibiotics.com.

	Abstract

The lack of novel antibiotics against Gram-negative bacteria has re-instated polymyxins as the drugs of last resort to treat serious infections caused by the extremely multiresistant Gram-negatives. However, polymyxins are nephrotoxic, and this may complicate the therapy or even require its discontinuation. In analogy to aminoglycosides, the nephrotoxicity of polymyxins might be related to the highly cationic nature of the molecule. Colistin and polymyxin B carry 5 positive charges. Here we show that novel polymyxin derivatives, carrying 3 positive charges only, are effective antibacterial agents. NAB739 has the cyclic peptide portion identical to that of polymyxin B, but in the linear portion of the peptide, it carries the threonyl-Dserinyl residue (no cationic charges) instead of the diaminobutyryl-threonyl-diaminobutyryl residue (2 cationic charges). The MIC values of NAB739 for 17 strains of E. coli were identical, or very close, to those of polymyxin B. Furthermore, NAB739 was effective against other polymyxin-susceptible strains of Enterobacteriaceae, and 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 2000. The affinities of the NAB compounds to isolated rat kidney brush border membrane were significantly lower than that of polymyxin B.