Researchers Find New Chemical Key That Could Unlock Hundreds Of New ...

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Chemistry researchers at The University of Warwick and the JohnInnes Centre, have found a novel signalling molecule that could bea key that will open up hundreds of new antibiotics unlocking themfrom the DNA of the Streptomyces family of bacteria. With bacterial resistance growing researchers are keen to uncoveras many new antibiotics as possible. Some of the Streptomycesbacteria are already used industrially to produce currentantibiotics and researchers have developed approaches to find andexploit new pathways for antibiotic production in the genome of theStreptomyces family. For many years it was thought that therelatively unstable butyrolactone compounds represented by"A-factor" were the only real signal for stimulating such pathwaysof possible antibiotic production but the Warwick and John Innesteams have now found a much more stable group of compounds that mayhave the potential to produce at least one new antibiotic compoundfrom up to 50% of the 1000 or so known Streptomyces family ofbacteria. Colonies of bacteria such as Streptomyces naturally makeantibiotics as a defence mechanism when those colonies are understress and thus more susceptible to attack from other bacteria. Thecolonies need to produce a compound to spread a signal across thecolony to start producing their natural antibiotic weapons. The amounts of such signalling material produced are incrediblysmall. Only micrograms of these compounds can be isolated byChemists and usually the available instrumentation needs at leastmilligrams of material to make a useful analysis. However theWarwick team was able to make use of the University of Warwick's700 MHz NMR machine to get a close look at just micrograms of 5 newpossible signalling compounds identified as2-alkyl-4-hydroxymethylfuran-3- carboxylic acids (or AHFCAs). The researchers, led by Dr Christophe Corre, and Professor GregChallis from the University of Warwick's Department of Chemistrywere able to combine their new insight into these compounds withthe relatively new full genetic sequences now available of someStreptomyces bacteria. They became convinced that the AHFCA groupof compounds could play a role in stimulating the production ofknown and novel antibiotics. When they added AHFCAs to Streptomycescoelicolor W81 they were proved correct as it stimulated theproduction of methylenomycin antibiotics. While the methylenomycins were already known as antibiotics, theresearchers think it likely that novel pathways for antibioticproduction are also under the control of AHFCAs. The AHFCAs shouldbe relatively easy to make in significant quantity in a lab andcould be used as a new tool for discovery of antibiotics. The researchers are now seeking funding to explore the AHFCAs anddevelop a novel approach for drug discovery. Introducing a varietyof AHFCAs to various Streptomyces bacteria could activate hundredsof pathways for antibiotic production. The lead researcher on the paper Dr Christophe Corre, from theUniversity of Warwick's Department of Chemistry said: "Early results also suggest that this approach could switch onnovel antibiotic production pathways in up to 50% of Streptomycesbacteria. With thousands of known members of the Streptomycesfamily that could mean that AHFCAs could unlock hundreds of newantibiotics to replenish our dwindling arsenal of effectiveantibiotic drugs." The full paper is entitled:"2-Alkyl-4-hydroxymethylfuran-3-carboxylic acids, antibioticproduction inducers discovered by Streptomyces coelicolor genomemining" by Christophe Corre, Lijiang Song, Sean O'Rourke, Keith F.Chater and Gregory L. Challis and is published in PNAS's olineedition. The University of Warwick