New chemical key could unlock hundreds of new antibiotics
12 November 2008
Researchers at The University of Warwick and the John Innes Centre,
UK, have found a novel signalling molecule that could be a key that will
open up hundreds of new antibiotics, unlocking them from the DNA of the
Streptomyces family of bacteria.
With bacterial resistance growing, researchers are keen to uncover as
many new antibiotics as possible. Some of the Streptomyces
bacteria are already used industrially to produce current antibiotics
and researchers have developed approaches to find and exploit new
pathways for antibiotic production in the genome of the Streptomyces
family.
For many years it was thought that the relatively unstable
butyrolactone compounds represented by 'A-factor' were the only real
signal for stimulating such pathways of possible antibiotic production
but the Warwick and John Innes teams have now found a much more stable
group of compounds that may have the potential to produce at least one
new antibiotic compound from up to 50% of the 1000 or so known
Streptomyces family of bacteria.
Colonies of bacteria such as Streptomyces naturally make
antibiotics as a defence mechanism when those colonies are under stress
and thus more susceptible to attack from other bacteria. The colonies
need to produce a compound to spread a signal across the colony to start
producing their natural antibiotic weapons.
The amounts of such signalling material produced are incredibly
small. Only micrograms of these compounds can be isolated by chemists
and usually the available instrumentation needs at least milligrams of
material to make a useful analysis.
The University of Warwick team, however, was able to make use of the
University's 700 MHz NMR machine to get a close look at just micrograms
of fiv e new possible signalling compounds identified as
2-alkyl-4-hydroxymethylfuran-3-carboxylic acids (or AHFCAs).
The researchers, led by Dr Christophe Corre, and Professor Greg
Challis from the University of Warwick’s Department of Chemistry were
able to combine their new insight into these compounds with the
relatively new full genetic sequences now available of some Streptomyces
bacteria.
They became convinced that the AHFCA group of compounds could play a
role in stimulating the production of known and novel antibiotics. When
they added AHFCAs to Streptomyces coelicolor W81 they were proved
correct as it stimulated the production of methylenomycin antibiotics.
While the methylenomycins were already known as antibiotics, the
researchers think it likely that novel pathways for antibiotic
production are also under the control of AHFCAs. The AHFCAs should be
relatively easy to make in significant quantity in a lab and could be
used as a new tool for discovery of antibiotics. The researchers are now
seeking funding to explore the AHFCAs and develop a novel approach for
drug discovery. Introducing a variety of AHFCAs to various
Streptomyces bacteria could activate hundreds of pathways for
antibiotic production.
The lead researcher on the paper Dr Christophe Corre, from the
University of Warwick’s Department of Chemistry said: “Early results
also suggest that this approach could switch on novel antibiotic
production pathways in up to 50% of Streptomyces bacteria. With
thousands of known members of the Streptomyces family that could
mean that AHFCAs could unlock hundreds of new antibiotics to replenish
our dwindling arsenal of effective antibiotic drugs.”
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