Bad News to Bad Bugs: Northern Antibiotics Develops Novel Polymyxins With Reduced Toxicity

Wednesday, July 2, 2008 General News
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HELSINKI, July 1 The emergence of multidrug-resistantGram-negative bacteria has necessitated the use of polymyxins as the agentsof last resort despite their known nephrotoxicity. Now Northern AntibioticsLtd, a Finnish biotech company, has developed novel polymyxin derivativeswhich in early preclinical studies show signs of lower nephrotoxicity.

The derivatives contain three positive charges only, while polymyxin Band colistin have five. They bind to the isolated brush-border membrane ofrat kidney at an affinity which is only 1/5-1/7 of that for polymyxin B. Invivo rat studies also show remarkable differences in parameters that areconsidered 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 ofaction. The lead compound of the first group, NAB 7061, sensitizes entericbacteria to other antibiotics. For example, it reduces the minimum inhibitoryconcentration (MIC) of clarithromycin for ESBL-producing strains ofEscherichia coli by a factor of 250-750. NAB 739, the lead compound of thesecond series, acts directly against enteric bacteria. For E. coli (includingESBL-producing strains) the MIC90 is identical to that of polymyxin B. WhileNAB 739 is already alone highly active against multidrug-resistant strains ofAcinetobacter baumannii, it also at very low subinhibitory concentrationssensitizes this bacterium to other antibiotics. A paper entitled "Novelpolymyxin derivatives carrying only three positive charges are effectiveantibacterial 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 anexperimental E. coli peritonitis model in mice, and we are now talking topotential partners to further develop and eventually commercialize these twolines of novel compounds," says Professor Martti Vaara, CEO and co-founder ofNorthern Antibiotics Ltd.

"The need for well-tolerated antibiotics that are active againstmultidrug-resistant Gram-negative bacteria is urgent. Enteric bacteria areresponsible for more than 80% of all the hospital infections caused byGram-negative bacteria, and now they are rapidly becoming resistant to mostantibiotics that are currently used to treat them. Plasmid-mediatedcarbapenemases, probably transferred from Klebsiella pneumoniae, have nowbeen found in E. coli, the clinically most important species of Gram-negativeenteric bacteria. Also plasmid-mediated methylases that cause resistance toall aminoglycosides have been encountered. Finally and quite alarmingly, asingle genetic element conferring transferable resistance to carbapenems,aminoglycosides and fluoroquinolones has been reported in K. pneumoniae. Onedoes not need to be very smart to guess what follows when these plasmidsbecome more common and the resulting extremely multidrug-resistant strainsstart to spread."

About Northern Antibiotics Ltd.

Founded in 2003 and headquartered in Helsinki, Finland, NorthernAntibiotics Ltd is engaged in the discovery and development of novelantibiotics against multidrug-resistant Gram-negative bacteria. For moreinformation, visit Dr. Barry Mason Business Development Consultant Email: Phone: +44(0)1625-858396 Mobile: +44(0)7713-261356

SOURCE Northern Antibiotics Ltd

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