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Antimicrobial Agents and Chemotherapy, September 2008, p. 3229-3236, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00405-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Novel Polymyxin Derivatives Carrying Only Three Positive Charges Are Effective Antibacterial Agents {triangledown}

Martti Vaara,1,2* John Fox,3 Günther Loidl,4 Osmo Siikanen,5 Juha Apajalahti,5 Frank Hansen,6 Niels Frimodt-Møller,6 Junya Nagai,7 Mikihisa Takano,7 and Timo Vaara1

Northern Antibiotics Ltd., FI-00720 Helsinki,1 Division of Clinical Microbiology, Helsinki University Hospital, FI-00029 HUSLAB, Helsinki,2 Alimetrics Ltd., FI-02920 Espoo, Finland,5 Alta Bioscience, University of Birmingham, Birmingham B15 2TT, United Kingdom,3 Bachem AG, CH-4416 Bubendorf, Switzerland,4 Statens Serum Institut, Copenhagen S, DK-2300, Denmark,6 Hiroshima University, Graduate School of Biomedical Sciences, Hiroshima 734-8553, Japan7

Received 25 March 2008/ Returned for modification 25 May 2008/ Accepted 22 June 2008

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.

* Corresponding author. Mailing address: Northern Antibiotics Ltd., Eskolantie 1, FI-00720 Helsinki, Finland. Phone: 358-50-355 0822. Fax: 358-9-6842 0130. E-mail: martti.vaara{at}northernantibiotics.com

{triangledown} Published ahead of print on 30 June 2008.

Antimicrobial Agents and Chemotherapy, September 2008, p. 3229-3236, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00405-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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