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 Vaara, CEO and
co-founder of Northern Antibiotics Ltd.
"The need for well-tolerated antibiotics that are active against
multidrug-resistant Gram-negative bacteria is urgent. Enteric bacteria are
responsible for more than 80% of all the hospital infections caused by
Gram-negative bacteria, and now they are rapidly becoming resistant to most
antibiotics that are currently used to treat them. Plasmid-mediated
carbapenemases, probably transferred from Klebsiella pneumoniae, have now
been found in E. coli, the clinically most important species of
Gram-negative enteric bacteria. Also plasmid-mediated methylases that cause
resistance to all aminoglycosides have been encountered. Finally and quite
alarmingly, a single genetic element conferring transferable resistance to
carbapenems, aminoglycosides and fluoroquinolones has been reported in K.
pneumoniae. One does not need to be very smart to guess what follows when
these plasmids become more common and the resulting extremely
multidrug-resistant strains start to spread."
About Northern Antibiotics Ltd.
Founded in 2003 and headquartered in Helsinki, Finland, Northern
Antibiotics Ltd is engaged in the discovery and development of novel
antibiotics against multidrug-resistant Gram-negative bacteria. For more
information, visit http://www.northernantibiotics.com.
Contact:
Dr. Barry Mason
Business Development Consultant
Email: barry.mason@northernantibiotics.com
Phone: +44(0)1625-858396
Mobile: +44(0)7713-261356
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[Via Healthcare]
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