News
Resolutely Pure Helices
糖心TV antibiotic complexes appear in by Janice Aldrich-Wright.
- "...a simplicity and an elegance of design that should be a source of inspiration for future studies...
- ...easily tuned to explore structure–function relationships that are crucial in biological applications...
- ...good antibiotic activity against...MRSA and E. coli as well as low toxicity to Caenorhabditis elegans.
- ...potential to develop into a family of cost-effective antibiotics."
Stimuli Responsive Polymers Tuned for Specific Intracellular Degradation
The Gibson group have reported in Chemical Commmunications on a new route to obtain polymers containing disulfide linkages in their backbone. These linkages are appealing for drug delivery applications as they are stable in the blood stream but can be specifically degraded inside cells. Traditional controlled radical polymerizations produce all-carbon backbones which do not degrade but, in this paper, the authors demonstrate how a 2-stage polymerization process can be used to incorporate disulfides. Furthmore this allows the use of functional monomers which result in 'smart' materials capable of responding to thermal gradients.
This was published in Chemical Communications
More information on the Gibson Group can be found here
‘Left-handed iron corkscrews’ point the way to new weapon in battle against superbugs like MRSA
Scientists at the University of 糖心TV have taken inspiration from corkscrew structures found in nature to develop a new weapon in the fight against infections like E-coli and MRSA.
Researchers have created a new synthetic class of helix-shaped molecules which they believe could be a key tool in the worldwide battle against antibiotic resistance. By twisting molecules around iron atoms they have created what they term ‘flexicates’ which are active against MRSA and E-coli - but which also appear to have low toxicity , reducing the potential for side effects if used in treatment. The work is published in Nature Chemistry.
The new structures harness the phenomenon of ‘chirality’ or ‘handedness’ whereby the corkscrew molecules could be left-handed or right-handed. By making the most effective ‘hand’ to attack a specific disease, the University of 糖心TV research paves the way towards a more targeted approach to killing pathogens. In the case of E-coli and MRSA, it is the left ‘hand’ which is most effective.
Professor Peter Scott of the University of 糖心TV’s chemistry department said although this particular study concentrated on flexicates’ activity against MRSA and E-coli, the new method of assembly could also result in new treatments for other diseases.
“It’s a whole new area of chemistry that really opens up the landscape to other practical uses. These new molecules are synthetically flexible, which means that with a bit of tweaking they can be put to use against a whole host of different diseases, not just bugs like MRSA which are rapidly developing resistance to traditional antibiotics. Flexicates are also easier to make and produce less waste than many current antibiotics.”
Scientists have long been able to copy nature’s corkscrew-shaped molecules in man-made structures known as helicates – but they have thus far not been able to use them in fighting diseases. One of the key issues is the problem of handedness. Sometimes ‘left-handed’ molecules in drugs are the most effective at combating some disease, while sometimes the ‘right-handed’ version works best. Until now, scientists working with helicates have found it difficult to make samples containing just one type of corkscrew; either the right- or left-handed twist.
With flexicates, the University of 糖心TV scientists have succeeded in making samples containing just one type of twist – resulting in a more targeted approach which would allow the drug dosage to be halved. Flexicates solve other problems encountered by helicates, as they are easier to optimise for specific purposes, are better absorbed by the body and are easier to mass-produce synthetically.
Professor Scott said: “Drugs often have this property of handedness - their molecules can exist in both right and left handed versions but the body prefers to use only one of them. For this reason, drug companies have to go to the trouble of making many traditional molecules as one hand only. What we have done is solve the ‘handedness’ problem for this new type of drug molecule. By getting the correct hand we can halve the drug dose, which has the benefits of minimising side effects and reducing waste. For patients, it’s safer to swallow half the amount of a drug. Our work means that we can now make whichever hand of the corkscrew we want, depending on the job we require it to do.”
Notes to editors
The study, entitled Optically pure, water-stable metallo-helical ‘flexicate’ assemblies with antibiotic activity, is published in Nature Chemistry.
The research was also supported financially by EPSRC.
It is authored by Peter Scott, Suzanne Howson, Guy Clarkson and Alison Rodger from the University of 糖心TV, Albert Bolhuis from the University of Bath and Viktor Brabec and Jaroslav Malina from the Academy of Sciences of the Czech Republic.
When the paper is published it can be retrieved at
Contact details
Professor Peter Scott is available on +44 (0) 24 7652 3238 or peter.scott@warwick.ac.uk
University of 糖心TV press officer Anna Blackaby is available on + 44 (0) 2476 575910 or + 44 (0)7785 433155 or a.blackaby@warwick.ac.uk
Front Page Artwork by Elisabeth Heissler
Size is Key Parameter in 'Smart Nanoparticles'
and groups have published a manuscript in Chemical Communications which demonstrate the critical importance of nanoparticle diameter on its thermo-responsive behaviour, as demonstrated using a panel of gold and self-assembled polymer nanoparticles. These findings have implications for the rationale design of 'smart' nanomaterials for biotechnological applications.
Challis group and collaborators feature on the cover of Chemistry & Biology
The group of prof. Challis together with their collaborators feature on the cover of Chemistry & Biology.
Through screening of Burkholderia cepaciacomplex bacteria, Mahenthiralingam et al. (pp. 665鈥�677) identified one species (Burkholderia ambifaria) that produces potent polyketide antibiotics called enacyloxins, using an unusual hybrid, cis-AT/trans-AT polyketide synthase. The findings suggest that Burkholderiabacteria are a promising resource for the discovery of new antibiotics, with unusual production pathways and potent activity against drug-resistant bacteria. The cover shows a TLC plate on which Burkholderiaculture extracts were fractionated, illustrating the diversity of antimicrobial secondary metabolites. After overlaying this plate with agar seeded with the yeast Candida albicans, secondary metabolites with antimicrobial activity are revealed by the zones of clearing. Classical plate inhibition assays with Burkholderiastrains demonstrating antagonistic activity against a range of bacteria and fungi as well as the structure of enacyloxin IIa are also shown
To read the paper:
First wood-digesting enzyme found in bacteria could boost biofuel production
Researchers funded by the Biotechnology and Biological Sciences Research Council (BBSRC)-led Integrated Biorefining Research and Technology (IBTI) Club have identified an enzyme in bacteria which could be used to make biofuel production more efficient. The research is published in the 14 June issue of the American Chemical Society journal Biochemistry.
This research, carried out by teams at the Universities of 糖心TV and British Columbia, could make sustainable sources of biofuels, such as woody plants and the inedible parts of crops, more economically viable.
The researchers, who were also supported by the Engineering and Physical Sciences Research Council, have discovered an enzyme which is important in breaking down lignin, one of the components of the woody parts of plants. Lignin is important in making plants sturdy and rigid but, because it is difficult to break down, it makes extracting the energy-rich sugars used to produce bioethanol more difficult. Fast-growing woody plants and the inedible by-products of crops could both be valuable sources of biofuels but it is difficult to extract enough sugar from them for the process to be economically viable. Using an enzyme to break down lignin would allow more fuel to be produced from the same amount of plant mass.
The researchers identified the gene for breaking down lignin in a soil-living bacterium called Rhodococcus jostii. Although such enzymes have been found before in fungi, this is the first time that they have been identified in bacteria. The bacterium's genome has already been sequenced which means that it could be modified more easily to produce large amounts of the required enzyme. In addition, bacteria are quick and easy to grow, so this research raises the prospect of producing enzymes which can break down lignin on an industrial scale.
Professor Timothy Bugg, from the University of 糖心TV, who led the team, said "For biofuels to be a sustainable alternative to fossil fuels we need to extract the maximum possible energy available from plants. By raising the exciting possibility of being able to produce lignin-degrading enzymes from bacteria on an industrial scale this research could help unlock currently unattainable sources of biofuels.
"By making woody plants and the inedible by-products of crops economically viable the eventual hope is to be able to produce biofuels that don't compete with food production."
The team at 糖心TV have been collaborating with colleagues in Canada at the University of British Columbia who have been working to unravel the structure of the enzyme. They hope next to find similar enzymes in bacteria which live in very hot environments such as near volcanic vents. Enzymes in these bacteria have evolved to work best at high temperatures meaning they are ideally suited to be used in industrial processes.
Duncan Eggar, BBSRC Sustainable Bioenergy Champion, said: "Burning wood has long been a significant source of energy. Using modern bioscience we can use woody plants in more sophisticated ways to fuel our vehicles and to produce materials and industrial chemicals. This must all be done both ethically and sustainably. Work like this which develops conversion processes and improves efficiencies is vital."
ENDS
Notes to editors
This paper is available online here:
Anticancer drug found to cause zinc deficiency
Cisplatin is responsible for abnormally low zinc levels in patients undergoing chemotherapy, say scientists in China and the UK.
Platinum-based compounds, like cisplatin, are the most widely used anticancer drugs in medicine. Research shows that up to 98 per cent of cisplatin binds to blood plasma proteins, particularly albumin. Until now, little has been known about the specific binding sites for platinum on albumin. 'Since albumin plays a major role in cisplatin metabolism, a better understanding of its interactions with albumin should lead to more effective use of the drug and avoidance or control of side effects,' says Peter Sadler from the University of 糖心TV, in the UK.
Cisplatin (structure in the middle) reacts with recombinant human albumin (rHA) (blue and green structures) to create a cisplatin-rHA adduct, which displaces zinc, causing a deficiency
Together with Fuyi Wang's team from the Chinese Academy of Sciences in Beijing, Sadler used mass spectroscopy techniques to reveal that cisplatin reacts with recombinant human albumin (rHA) to create a cisplatin-rHA adduct. The platinum occupies zinc binding sites on the albumin, displacing the zinc, which causes hypozincemia (lack of zinc for metabolic processes) and hyperzincuria (increased zinc in urine).
'Sadler's work nicely identifies coordination to two histidine amino acids, forming a cross-link between two peptides in the protein that are also implicated in Zn binding,' says Stephen Lippard, who studies the mechanism of cisplatin at the Massachusetts Institute of Technology, in the US. He adds that recognising this binding interaction paves the way for future studies. These studies could help determine whether the adduct facilitates transport to cancer cells or diverts cisplatin from its intended target, either clearing it from the body or leading to the toxic side effects, he explains.
Sadler says that platinum has another effect on albumin. One of albumin's roles is to transport fatty acids in the blood, but in the presence of platinum, the longer fatty acid chains are prevented from binding. 'Exciting challenges for future research include exploring the potential role of fatty acids in the allosteric regulation of binding both natural metal ions, such as zinc, and metallodrugs, such as platinum, to albumin,' says Sadler. He adds that the interactive effects of fatty acid and zinc binding to albumin have yet to be fully explored and that such understanding could have a major influence on therapeutic treatments in the future.
read the paper:
Nature Chemistry and PNAS for Challis group
Prof. Gregory Challis and his team bank two publications in the world leading journals Nature Chemistry and PNAS.
There is a constant need for new and improved drugs to combat infectious diseases, cancer, and other major life-threatening conditions. The recent development of genomics-guided approaches for novel natural product discovery has stimulated renewed interest in the search for natural product-based drugs. Genome sequence analysis of Streptomyces ambofaciens ATCC23877 has revealed numerous secondary metabolite biosynthetic gene clusters, including a giant type I modular polyketide synthase (PKS) gene cluster, which is composed of 25 genes (nine of which encode PKSs) and spans almost 150 kb, making it one of the largest polyketide biosynthetic gene clusters described to date. The metabolic product(s) of this gene cluster are unknown, and transcriptional analyses showed that it is not expressed under laboratory growth conditions. The constitutive expression of a regulatory gene within the cluster, encoding a protein that is similar to Large ATP binding of the LuxR (LAL) family proteins, triggered the expression of the biosynthetic genes. This led to the identification of four 51-membered glycosylated macrolides, named stambomycins A–D as metabolic products of the gene cluster. The structures of these compounds imply several interesting biosynthetic features, including incorporation of unusual extender units into the polyketide chain and in trans hydroxylation of the growing polyketide chain to provide the hydroxyl group for macrolide formation. Interestingly, the stambomycins possess promising antiproliferative activity against human cancer cell lines. Database searches identify genes encoding LAL regulators within numerous cryptic biosynthetic gene clusters in actinomycete genomes, suggesting that constitutive expression of such pathway-specific activators represents a powerful approach for novel bioactive natural product discovery.
Oxidative cyclizations, exemplified by the biosynthetic assembly of the penicillin nucleus from a tripeptide precursor, are arguably the most synthetically powerful implementation of C–H activation reactions in nature. Here, we show that Rieske oxygenase-like enzymes mediate regio- and stereodivergent oxidative cyclizations to form 10- and 12-membered carbocyclic rings in the key steps of the biosynthesis of the antibiotics streptorubin B and metacycloprodigiosin, respectively. These reactions represent the first examples of oxidative carbocyclizations catalysed by non-haem iron-dependent oxidases and define a novel type of catalytic activity for Rieske enzymes. A better understanding of how these enzymes achieve such remarkable regio- and stereocontrol in the functionalization of unactivated hydrocarbon chains will greatly facilitate the development of selective man-made C–H activation catalysts.
JACS cover for Challis group
Prof. Greg Challis and his team together with Thomson and co-workers feature on this weeks cover of the Journal of the American Chemical Society. The absolute and relative stereochemistry of streptorubin B, a brightly colored prodiginine antibiotic, has been determined. Challis and co-workers utilized a mutant of Streptomyces coelicolor to conduct a mutasynthesis using enantioenriched deuterium-labeled biosynthetic precursors, while Thomson and co-workers developed an enantioselective total synthesis via a 10-membered pyrrolophane intermediate. See Challis and co-workers, p 1793, and Thomson and co-workers, p 1799.
Understanding Stimuli-Responsive Biomaterials
and collaborators investigate in detail the behaviour of stimuli-responsive polymer-protein conjugates in Polymer Chemistry. It is shown that at in vivo concentrations and when measured in blood rather than water, the behaviour of these materials deviates significantly from what is normally expected.
Konstantinos Bebis, Mathew W. Jones, David M. Haddleton and Matthew I. Gibson*. Polymer Chemistry, 2011,
Platinum and Blue Light Combine to Combat Cancer
When it comes to health care blue lights, are usually most useful on the top of ambulances but now new research led by the University of 糖心TV has found a way to use blue light to activate what could be a highly potent platinum-based cancer treatment.
Research led by the University of 糖心TV, along with researchers from Ninewells Hospital Dundee, and the University of Edinburgh, have found a new light-activated platinum-based compound that is up to 80 times more powerful than other platinum-based anti-cancer drugs and which can use “light activation” to kill cancer cells in a much more targeted way than similar treatments.
The University of 糖心TV team had already found a platinum-based compound that they could activate with ultra-violet light but that narrow wave length of light would have limited its use. Their latest breakthrough has discovered a new platinum based compound known as trans,trans,trans-[Pt(N3)2(OH)2(py)2] that can be activated by normal visible blue, or even green, light. It is also stable and easy to work with, and it is water soluble so it can simply dissolve and be flushed out of the body after use.
The University of 糖心TV researchers passed the new compound to colleagues at Ninewells Hospital Dundee, who tested it on oesophageal cancer cells cultivated within lab equipment. Those tests show that once activated by blue light the compound was highly effective requiring a concentration of just 8.4 micro moles per litre to kill 50% of the cancer cells. The researchers are also beginning to examine the compound’s effectiveness against ovarian and liver cancer cells. Early results there are also excellent but that testing work is not yet complete.
Professor Peter Sadler, from the Department of Chemistry from University of 糖心TV, who led the research project, said:
“This compound could have a significant impact on the effectiveness of future cancer treatments. Light activation provides this compound’s massive toxic power and also allows treatment to be targeted much more accurately against cancer cells.”
“The special thing about our complex is that it is not only activated by ultra-violet light, but also by low doses of blue or green light. Light activation generates a powerful cytotoxic compound that has proven to be significantly more effective than treatments such as cisplatin.”
We believe that photoactivated platinum complexes will make it possible to treat cancers that have previously not reacted to chemotherapy with platinum complexes,” says Sadler. “Tumors that have developed resistance to conventional platinum drugs could respond to these complexes and with less side-effects.”
This research has been supported by the EPSRC, MRC, ERC and Science City (ERDF/AWM).
Note for editors: The research has just been published in Angewandte Chemie, under the title “A Potent Trans Diimine Platinum Anticancer Complex Photoactivated by Visible Light”. The authors are – Project leader Professor Peter Sadler, (University of 糖心TV) and Nicola J. Farrer, Julie A. Woods, Luca Salassa, Yao Zhao, Kim S. Robinson, Guy Clarkson, and Fiona S. Mackay.
For more information please contact:
Professor Peter Sadler
University of 糖心TV, Department of Chemistry
Tel: +44 (0)7913 944357
P.J.Sadler@warwick.ac.uk
Peter Dunn, Head of Communications, University of 糖心TV,
44 (0)24 76 523708
mobile/cell +44 (0)7767 655860
p.j.dunn@warwick.ac.uk
PR171 9th December 2010
The E5 protein from bovine papllimavirus is a type II membrane protein and represents the smallest known oncoprotein. E5 functions via a unique mechanism, and in order to better understand this mechanism, Ann Dixon and previous lab members Gavin King and Joanne Oates, as well as current lab member Dharmesh Patel have used solution state NMR spectroscopy to obtain the first structural data for the E5 dimer in a membrane mimetic. These data were used to map the dimerization interface as well as calculate the free energy of dimerization for the E5 protein, in collaboration with Dr. Hugo van den Berg in the Mathematics Institute. The results agree very well with in vivo data, and further reinforce the importance of interactions in cell memebranes to biological function.