Tag Archives: Alan Cockayne

Antibiotic synthetic spider silk

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I have a couple of questions, what is ‘click’ chemistry and how does a chance meeting lead to a five-year, interdisciplinary research project on synthetic spider silk? From a Jan. 4, 2017 news item on ScienceDaily,

A chance meeting between a spider expert and a chemist has led to the development of antibiotic synthetic spider silk.

After five years’ work an interdisciplinary team of scientists at The University of Nottingham has developed a technique to produce chemically functionalised spider silk that can be tailored to applications used in drug delivery, regenerative medicine and wound healing.

The Nottingham research team has shown for the first time how ‘click-chemistry’ can be used to attach molecules, such as antibiotics or fluorescent dyes, to artificially produced spider silk synthesised by E.coli bacteria. The research, funded by the Biotechnology and Biological Sciences Research Council (BBSRC) is published today in the online journal Advanced Materials.

A Jan. 3, 2016 University of Nottingham press release (also on EurekAlert), which originated the news item, provides a few more details about ‘click’ chemistry (not enough for me) and more information about the research,

The chosen molecules can be ‘clicked’ into place in soluble silk protein before it has been turned into fibres, or after the fibres have been formed. This means that the process can be easily controlled and more than one type of molecule can be used to ‘decorate’ individual silk strands.

Nottingham breakthrough

In a laboratory in the Centre of Biomolecular Sciences, Professor Neil Thomas from the School of Chemistry in collaboration with Dr Sara Goodacre from the School of Life Sciences, has led a team of BBSRC DTP-funded PhD students starting with David Harvey who was then joined by Victor Tudorica, Leah Ashley and Tom Coekin. They have developed and diversified this new approach to functionalising ‘recombinant’ — artificial — spider silk with a wide range of small molecules.

They have shown that when these ‘silk’ fibres are ‘decorated’ with the antibiotic levofloxacin it is slowly released from the silk, retaining its anti-bacterial activity for at least five days.

Neil Thomas, a Professor of Medicinal and Biological Chemistry, said: “Our technique allows the rapid generation of biocompatible, mono or multi-functionalised silk structures for use in a wide range of applications. These will be particularly useful in the fields of tissue engineering and biomedicine.”

Remarkable qualities of spider silk

Spider silk is strong, biocompatible and biodegradable. It is a protein-based material that does not appear to cause a strong immune, allergic or inflammatory reaction. With the recent development of recombinant spider silk, the race has been on to find ways of harnessing its remarkable qualities.

The Nottingham research team has shown that their technique can be used to create a biodegradable mesh which can do two jobs at once. It can replace the extra cellular matrix that our own cells generate, to accelerate growth of the new tissue. It can also be used for the slow release of antibiotics.

Professor Thomas said: “There is the possibility of using the silk in advanced dressings for the treatment of slow-healing wounds such as diabetic ulcers. Using our technique infection could be prevented over weeks or months by the controlled release of antibiotics. At the same time tissue regeneration is accelerated by silk fibres functioning as a temporary scaffold before being biodegraded.”

The medicinal properties of spider silk recognised for centuries.

The medicinal properties of spider silk have been recognised for centuries but not clearly understood. The Greeks and Romans treated wounded soldiers with spider webs to stop bleeding. It is said that soldiers would use a combination of honey and vinegar to clean deep wounds and then cover the whole thing with balled-up spider webs.

There is even a mention in Shakespeare’s Midsummer Night’s Dream: “I shall desire you of more acquaintance, good master cobweb,” the character ‘Bottom’ said. “If I cut my finger, I shall make bold of you.”

The press release goes on to describe the genesis of the project and how this multidisciplinary team was formed in more detail,

The idea came together at a discipline bridging university ‘sandpit’ meeting five years ago. Dr Goodacre says her chance meeting at that event with Professor Thomas proved to be one of the most productive afternoons of her career.

Dr Goodacre, who heads up the SpiderLab in the School of Life Sciences, said: “I got up at that meeting and showed the audience a picture of some spider silk. I said ‘I want to understand how this silk works, and then make some.’

“At the end of the session Neil came up to me and said ‘I think my group could make that.’ He also suggested that there might be more interesting ‘tweaks’ one could make so that the silk could be ‘decorated’ with different, useful, compounds either permanently or which could be released over time due to a change in the acidity of the environment.”

The approach required the production of the silk proteins in a bacterium where an amino acid not normally found in proteins was included. This amino acid contained an azide group which is widely used in ‘click’ reactions that only occur at that position in the protein. It was an approach that no-one had used before with spider silk — but the big question was — would it work?

Dr Goodacre said: “It was the start of a fascinating adventure that saw a postdoc undertake a very preliminary study to construct the synthetic silks. He was a former SpiderLab PhD student who had previously worked with our tarantulas. Thanks to his ground work we showed we could produce the silk proteins in bacteria. We were then joined by David Harvey, a new PhD student, who not only made the silk fibres, incorporating the unusual amino acid, but also decorated it and demonstrated its antibiotic activity. He has since extended those first ideas far beyond what we had thought might be possible.”

David Harvey’s work is described in this paper but Professor Thomas and Dr Goodacre say this is just the start. There are other joint SpiderLab/Thomas lab students working on uses for this technology in the hope of developing it further.

David Harvey, the lead author on this their first paper, has just been awarded his PhD and is now a postdoctoral researcher on a BBSRC follow-on grant so is still at the heart of the research. His current work is focused on driving the functionalised spider silk technology towards commercial application in wound healing and tissue regeneration.

Here’s a link to and a citation for the paper,

Antibiotic Spider Silk: Site-Specific Functionalization of Recombinant Spider Silk Using “Click” Chemistry by David Harvey, Philip Bardelang, Sara L. Goodacre, Alan Cockayne, and Neil R. Thomas. Advanced Materials DOI: 10.1002/adma.201604245 Version of Record online: 28 DEC 2016

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

This paper is behind a paywall.

I imagine Mr. Cockayne’s name has led to much teasing over the years. People who have names with that kind of potential tend to either change them or double down and refuse to compromise.

Don’t kill bacteria, uninvite them

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The relentless campaign against bacteria has had some unintended consequences, we’ve made bacteria more resistant and more virulent. Researchers at the University of Nottingham (UK) have taken a different approach from attempting to eradicate or kill; they’ve discovered a class of polymers that ‘uninvites’ bacteria from their surfaces. From the Aug. 13, 2012 news item on ScienceDaily,

Using state-of-the-art technology, scientists at The University of Nottingham have discovered a new class of polymers that are resistant to bacterial attachment. These new materials could lead to a significant reduction in hospital infections and medical device failures.

Medical device associated infections can lead to systemic infections or device failure, costing the NHS £1bn a year. Affecting many commonly used devices including urinary and venous catheters — bacteria form communities known as biofilms. This ‘strength in numbers approach’ protects them against the bodies’ natural defences and antibiotics.

Experts in the Schools of Pharmacy and Molecular Medical Sciences, have shown that when the new materials are applied to the surface of medical devices they repel bacteria and prevent them forming biofilms.

There’s a video of the scientists discussing their work on this new class of polymers,

In order to find this new class of polymers, the scientists had to solve another problem first. From the Aug. 12, 2012 University of Nottingham press release,

Researchers believed there were new materials that could resist bacteria better but they had to find them. This meant screening thousands of different chemistries and testing their reaction to bacteria — a challenge which was beyond conventional materials development or any of our current understanding of the interaction of micro-organisms with surfaces.

The discovery has been made with the help of experts from the Massachusetts Institute of Technology (MIT) — who initially developed the process by which thousands of unique polymers can now be screened simultaneously.

Professor Alexander said: “This is a major scientific breakthrough — we have discovered a new group of structurally related materials that dramatically reduce the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). We could not have found these materials using the current understanding of bacteria-surface interactions. The technology developed with the help of MIT means that hundreds of materials could be screened simultaneously to reveal new structure-property relationships. In total thousands of materials were investigated using this high throughput materials discovery approach leading to the identification of novel materials resisting bacterial attachment. This could not have been achieved using conventional techniques.”

Once they found this new class of polymers, researchers tested for effectiveness (from the Aug. 12, 2012 university press release),

These new materials prevent infection by stopping biofilm formation at the earliest possible stage — when the bacteria first attempt to attach themselves to the device. In the laboratory experts were able to reduce the numbers of bacteria by up to 96.7per cent — compared with a commercially available silver containing catheter — and were effective at resisting bacterial attachment in a mouse implant infection model. By preventing bacterial attachment the body’s own immune system can kill the bacteria before they have time to generate biofilms.

You can read more about this work in the paper the researchers have published (as well as, the news item on ScienceDaily or the University of Nottingham press release for more accessible explanations). You will need to get past a paywall (from the news item on ScienceDaily),

Andrew L Hook, Chien-Yi Chang, Jing Yang, Jeni Luckett, Alan Cockayne, Steve Atkinson, Ying Mei, Roger Bayston, Derek J Irvine, Robert Langer, Daniel G Anderson, Paul Williams, Martyn C Davies, Morgan R Alexander. Combinatorial discovery of polymers resistant to bacterial attachment. Nature Biotechnology, 2012; DOI: 10.1038/nbt.2316

This research reminded me of Sharklet, a product being developed in the US for use in hospitals. Designed to mimic sharkskin, the product discourages bacteria from settling on its surface. It was featured in my Feb. 10, 2011 posting.