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Bad News to Bad Bugs: Northern Antibiotics Develops Novel Polymyxins With Reduced Toxicity
Date:7/1/2008

HELSINKI, July 1 /PRNewswire/ -- The emergence of multidrug-resistant Gram-negative bacteria has necessitated the use of polymyxins as the agents of last resort despite their known nephrotoxicity. Now Northern Antibiotics Ltd, a Finnish biotech company, has developed novel polymyxin derivatives which in early preclinical studies show signs of lower nephrotoxicity.

The derivatives contain three positive charges only, while polymyxin B and colistin have five. They bind to the isolated brush-border membrane of rat kidney at an affinity which is only 1/5-1/7 of that for polymyxin B. In vivo rat studies also show remarkable differences in parameters that are considered to indicate early kidney damage, such as serum urea nitrogen, albuminuria and cylindrouria.

The derivatives fall in to two groups that differ in their mode of action. The lead compound of the first group, NAB 7061, sensitizes enteric bacteria to other antibiotics. For example, it reduces the minimum inhibitory concentration (MIC) of clarithromycin for ESBL-producing strains of Escherichia coli by a factor of 250-750. NAB 739, the lead compound of the second series, acts directly against enteric bacteria. For E. coli (including ESBL-producing strains) the MIC90 is identical to that of polymyxin B. While NAB 739 is already alone highly active against multidrug-resistant strains of Acinetobacter baumannii, it also at very low subinhibitory concentrations sensitizes this bacterium to other antibiotics. A paper entitled "Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents" was published ahead of print on June 30, 2008 (Antimicrob. Agents Chemother., doi:10.1128/AAC.00405-08).

"The efficacy of both lead compounds has been verified using an experimental E. coli peritonitis model in mice, and we are now talking to potential partners to further develop and eventually commercialize these two lines of novel compounds," says Professor Martti V
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SOURCE Northern Antibiotics Ltd
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