Researchers find new chemical key that could unlock hundreds of new antibiotics

October 29, 2008

Chemistry researchers at The University of Warwick and the John Innes Centre, 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. However the Warwick team was able to make use of the University of Warwick's 700 MHz NMR machine to get a close look at just micrograms of 5 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."

University of Warwick

---

---

	Streptomyces in Nature and Medicine: The Antibiotic Makers by David A. Hopwood (Author) This is an insiders account of 50 years of genetic studies of the soil-inhabiting microbes that produce most of the antibiotics used to treat infections, as well as anti-cancer, anti-parasitic and immunosuppressant drugs. The book begins by describing how these microbes the actinomycetes were discovered in the latter part of the nineteenth century, but remained a Cinderella group until, in the 1940s, they shot to prominence with the discovery of streptomycin, the first effective treatment for tuberculosis and only the second antibiotic, after penicillin, to become a medical marvel. There followed a massive effort over several decades to find further treatments for infectious diseases and cancer, tempered by the rise of antibiotic resistance consequent on antibiotic misuse and over-use....
	Streptomyces: Molecular Biology and Biotechnology by Paul Dyson (Editor) Streptomycetes are unusually complex bacteria that are abundant in soil. They grow as branching filaments and form chains of spores. Most importantly, they have an extraordinary ability to make antibiotics, for which they are the main industrial source, as well as other metabolites with medicinal properties. In recent years, the search for new antibiotics and other drugs in streptomycetes has been augmented by genomic studies, genome mining, and new biotechnological approaches. With contributions from some of the leading scientists in the field, this book documents recent research and development in streptomycetes genomics, physiology, and metabolism. With a focus on biotechnology and genomics, the book provides an excellent source of up-to-date information. Topics include: genome...
	Streptomyces Griseus: Webster's Timeline History, 1948 - 2007 by Icon Group International (Author) Webster's bibliographic and event-based timelines are comprehensive in scope, covering virtually all topics, geographic locations and people. They do so from a linguistic point of view, and in the case of this book, the focus is on "Streptomyces Griseus," including when used in literature (e.g. all authors that might have Streptomyces Griseus in their name). As such, this book represents the largest compilation of timeline events associated with Streptomyces Griseus when it is used in proper noun form. Webster's timelines cover bibliographic citations, patented inventions, as well as non-conventional and alternative meanings which capture ambiguities in usage. These furthermore cover all parts of speech (possessive, institutional usage, geographic usage) and contexts, including pop...
	Genetics and Product Formation in Streptomyces (F.E.M.S. Symposium Series) by Simon Baumberg (Editor), Hans Krügel (Editor), Dieter Noack (Editor)
	Nocardia and streptomyces: Proceedings of the International Symposium on Nocardia and Streptomyces, Warsaw, October 4-8, 1976 (Zentralblatt fur ... und Hygiene : 1. Abt. : Supplemente ; 6) by Fischer (Publisher)
	Cell - Volume 65 Number 4, May 17, 1991: Extracellular Complementation in Streptomyces by Benjamin: Editor Lewin (Author)
	Atlas of Ultrastructure of Streptomyces in Course of Biosynthesis of Antibiotics by W., et al Kurylowicz (Author)
	Ferulic acid esterase production by Streptomyces sp. [An article from: Bioresource Technology] by G. Mukherjee (Author), R.K. Singh (Author), A. Mitra (Author), S.K. Sen (Author) This digital document is a journal article from Bioresource Technology, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Studies were carried out on ferulic acid esterase production using a culture of Streptomyces S"1"0. In optimized condition, enzyme yield was 2.0mU/ml in MBS medium, containing 1.5% de-starched wheat bran at 30^oC and initial pH 6.5 under agitated submerged culture.
	Release of ferulic acid and feruloylated oligosaccharides from sugar beet pulp by Streptomyces tendae [An article from: Bioresource Technology] by P. Ferreira (Author), N. Diez (Author), C.B. Faulds (Author), J. Soliveri (Author), Co (Author) This digital document is a journal article from Bioresource Technology, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Given several promising industrial applications of ferulic acid, this study was designed to identify actinomycete strains able to release high levels of this acid from sugar beet pulp (SBP). Out of 47 strains tested, 37% were found to release free ferulic acid from the growth substrate. One strain, identified as Streptomyces tendae by 16S RNA gene sequencing, was capable of releasing 80% of the ferulic acid ester-linked to the pectin in SBP after 5 days of growth. These data suggest that some actinomycetes are...
	Lindane uptake and degradation by aquatic Streptomyces sp. strain M7 [An article from: International Biodeterioration & Biodegradation] by C.S. Benimeli (Author), G.R. Castro (Author), A.P. Chaile (Author), Amoroso (Author) This digital document is a journal article from International Biodeterioration & Biodegradation, published by Elsevier in 2007. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser. Description: Five actinomycete strains isolated from pesticide-contaminated sediments were able to grow in the presence of 10@mgl^-^1 lindane, an organochlorine pesticide. The strain growing best in the presence of lindane as the only carbon source was identified as Streptomyces sp. M7. After 96h of incubation in synthetic medium containing lindane and glucose, both substrates were simultaneously consumed; glucose 6.0gl^-^1 improved lindane degradation and obtained biomass. When Streptomyces sp. M7...