Salmonella research provides clues to antibiotic development
One major difficulty for developers of antibiotics is
choosing the proper point of attack against bacteria. There are hundreds of
possible points of attack, according to genome analysis and laboratory culture
experiments - but validation in in vivo infection models is largely lacking.
Infection biologists and proteomics researchers from Hannover Medical
School and the Max Planck Institute for Infection Biology have now identified
all the proteins involved in Salmonella metabolic paths during an infection. The
scientists isolated Salmonella from infected mice and then turned to
highly-sensitive mass spectrometry to look at the protein mixture - and
discovered hundreds of different Salmonella metabolic path proteins.
compared them with special protein databanks and identified possible points of
attack for antibiotics. The researchers examined what role these proteins play
in a Salmonella infection.
They turned off genes responsible for the
proteins to see how it affected the disease's progress. "Knocking out" the gene
was equivalent to blocking its corresponding metabolic path, thereby simulating
the effect of antibiotics.
The analysis demonstrated that in the two possible
types of salmonella-related illness (diarrhoea and typhoid), the bacteria are
surprisingly unaffected by the blockade of several central metabolic pathways.
The reason for this is redundant enzymes, as well as the host offering a
wide range of nutrients, which means Salmonella does not depend on its own
Only a few enzymes in certain metabolic pathways are
really necessarily to keep Salmonella bacteria alive. Most of these essential
enzymes are missing in other important pathogens, or they are also present in
the human organism, so they cannot be considered possible points of attack for
new broad-spectrum antibiotics with a wide range of effectiveness.
remaining potentially useful metabolic paths are already used as the targets of
current antibiotics - or have already been considered for development of an
A comprehensive analysis of two infection models -
typhoid and diarrhoea - shows clearly that there are far fewer than expected
possible points of attack for developing urgently needed antibiotics. It is also
now obvious that increasingly ineffective antibiotics ought to be replaced by
similar, but not identical, active principles. This points the way for future
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