Two new publications on Antifungal Surface Coatings

I’d like to highlight the great work from PhD student Javad Naderi.

Javad has published two papers on antifungal surface coatings.

The first, published in the Journal of Antimicrobial Chemotherapy, is on covalent coupling of two members of the echinocandin antifungal drug glass to surfaces. Both anidulafungin and micafungin surface coatings were highly antifungal vs Candida albicans.

Link to journal article. doi.org/10.1093/jac/dky437

Surface coatings with covalently attached anidulafungin and micafungin prevent Candida albicans biofilm formation. doi.org/10.1093/jac/dky437

However, perhaps the most important finding was that the anidulafungin surface killed yeast and prevented biofilm, and could be washed and rechallenged at least 5 times without losing efficacy.

This finding supports a mechanism of action where the drug is:

  • not eluted or cleaved from the surface
  • not affected by surface fouling

Along with previous publications on the other approved echinocandin, caspofungin, there is more evidence to suggest that the echinocandin drug class can be antifungal even when immobilised on surfaces (i.e. does not need diffusion to reach drug targets). Exactly how this happens is an active area or research for us.

The second explores the surface activity of another drug class, the polyenes. At first, it looks like drugs like amphotericin B remain active when attached to surfaces; however, if you are careful and you make sure to wash off ALL traces of loosely adsorbed compounds (leaving only contently attached) then this effect is eliminated.

Thus, not all surface coatings prepared using covalent attachment of antifungal drugs actually work.

Link to article: doi.org/10.1116/1.5050043

Surface-grafted antimicrobial drugs: Possible misinterpretation of mechanism of action. doi.org/10.1116/1.5050043

Failure to account for compounds that can be washed off and possible misinterpretation of mechanism of action should be an issue that researchers are made aware of.

This article was a Featured Article and a Scilight published in the journal Biointerphases.

 

 

The Importance of Fungal Pathogens and Antifungal Coatings in Medical Device Infections

How can we improve medical implants so that they combat microbial colonization and reduce the problem of implant-associated infections?

Basic science approaches for the design antimicrobial surfaces and coatings has been reviewed but it is clear that attention for fungal pathogens has been missing.

Fungal pathogens are important because they

  • Are misunderstood and underdiagnosed.
  • Severely affect immunocompromised and paediatric patients, and the elderly.
  • Are difficult to combat because antifungal agents tend to be toxic to human cells.

We have published a new review entitled The Importance of Fungal Pathogens and Antifungal Coatings in Medical Device Infections.

 https://www.sciencedirect.com/science/article/pii/S0734975017301520

The Importance of fungal pathogens and antifungal coatings in medical device infections

The review article is online now. Click the image to go to the website.

Highlights include:

  • Summary and evaluation of materials that release antifungal drugs and compounds.
  • Evaluation of the spectre of antimicrobial resistance (AMR) for fungi.
  • And provides critical discussion of the limitations in the field, with expert commentary on the future of the topic, as we see it, in the next five years, and then beyond.

This review is a significant addition to our 2014 review Biomaterials surfaces capable of resisting fungal attachment and biofilm formation. Biotech Adv. 2014; 32: 296-307.

This was a massive team effort that progressed over the course of one year. Our team of five authors wrote 17 pages of printed text and reviewed 89 references. This is the most comprehensive and up-to-date review in the field. We hope that the discussion on materials design will become an invaluable resource for researchers and feed into broader thinking about the wider field of design of antimicrobial biomaterials and polymicrobial biofilms.

Overview

Materials strategies for incorporating antifungals onto and into biomaterials.

Antifungal surfaces go 3D

We have continued our investigation on coatings that could be used to combat deadly fungal infections. Implanted medical devices can become colonised by the fungal yeast Candida albicans despite sterilisation procedures. Therefore, a medical device with a surface modification that could kill Candida on contact may help to reduce infection and death from these infections.

Previously we have shown that the antifungal drug caspofungin can be attached to medical-grade plastics using an ultra-thin surface layer only 20 nm thick. Because this coating is thin and flat, the caspofungin molecules essentially form a flat layer (approximately a 2 dimensional surface).

Our latest research has investigated the possibility of instead attaching caspofungin on polymer brushes. This allows the drug to be presented on flexible polymer linkers, extending hundreds of nanometres from the surface, and would improve the way the drug interacts with the fungal cell wall.

Depiction of the reaction steps, combining plasma polymerization and ARGET-ATRP to covalently attach amine-containing drugs, such as caspofungin, to surface-grafted PHEMA.

This is an important advancement in helping us to understand how surface-immobilised drugs interact with the fungal cell wall. We will use this information to understand how antibiotics work mecahanistically – that is, how tethered drugs would be able to penetrate into the cell wall and find their target of action which ends up killing the cell. Finding new mechanisms of action for antibiotic drugs could be one way that we can find new uses for a dwindling supply of effective antibiotic agents.

The work has been published in the journal Biointerphases and is an “Editor’s Pick”. This article is freely accessible through open access publishing.

We gratefully acknowledge the Australian Research Council for funding. (Discovery Project DP150101674. “Combating fungal biofilm growth on surfaces”.)

How to improve chemical functionality in deposited films

Our ARC Discovery Project (“Order from Chaos“) is aimed toward discovering how to improve polymer surface coatings — such as those that will be useful in advanced manufacturing of new materials. In the previous post, I discussed the discovery of how to make functional coatings from one chemical compound EBiB. Our latest published research describes a systematic investigation of three similar chemical compounds and is working towards establishing more general rules that could be applied more widely.

MIB EIB ETMA

Using structurally-related esters, lead author Solmaz Saboohi found the plasma deposition could proceed either through the α regime (lower pressure, collisional) or through the γ regime (higher pressure, collisionless). Analysis of the plasma phase and the deposited films showed noticeable differences under either conditions and markedly different coatings produced.

This discovery is helping us to understand the deposition characteristics of small molecular weight esters, which will hopefully be extended and generalised towards other compounds in the future.

Results have been recently published in the Royal Society of Chemistry journal Physical Chemistry Chemical Physics.

Link to article on publisher’s site.

Phys chem chem phys

 

Peering into the Plasma Black Box

Plasma polymerization has sometimes been a called a black art. How else to describe a process that takes a well-defined chemical structure, puts it in an electric field and shakes it about at 1 million times per second until it brightly glows and then chuck it at a surface and see what forms?

A poorly-controlled plasma polymerization might be imagined like this:

plasma

But how to control this process? During high-energy reactions, how do we prevent the formation of random polymer spaghetti? And can we figure out the rules for forming better defined plasma polymers with increased functional group retention?

plasma

While this example is greatly oversimplified, it emphasizes the point that when we use a well-controlled bolt of lightning to make surface coatings (albeit a cold one), we would rather have a less chaotic “scrambling” of the chemical in favour of more ordered and controlled deposits. The whole purpose of this is so that we can then use the intact bromine motif to perform other chemical reactions off of the surface.

I wrote about our ARC Discovery Grant “Order from Chaos” previously. With this project, we hope to discover some more fundamental rules that allow us to understand how to prepare functional polymeric coatings from fragile chemical precursors.

Our latest publication describes progress towards this aim as we try and write the lost instructions for the plasma black box. Here, lead author Solmaz Saboohi and the team from the Future Industries Institute describe new understanding arising from the use of analytical instrumentation to probe and compare the plasma phase and the resulting surface deposit that allows for “soft landing” of the excited chemical fragments. Contrary to conventional wisdom, using higher pressures — instead of lower ones — allows for better structural retention. In this regime, hyperthermal ions dominate in the plasma phase and are deposited to form plasma polymers with increased functionality.

You can find the publication here. Also, the article is open access.

Hyperthermal Intact Molecular Ions Play Key Role in Retention of ATRP Surface Initiation Capability of Plasma Polymer Films from Ethyl α-Bromoisobutyrate

Saboohi, S.; Coad, B. R.; Michelmore, A.; Short, R. D.; Griesser, H. J. Hyperthermal Intact Molecular Ions Play Key Role in Retention of ATRP Surface Initiation Capability of Plasma Polymer Films from Ethyl α-Bromoisobutyrate. ACS applied materials & interfaces 2016, 10.1021/acsami.6b04477.

 

Where are we heading with anti-infective medical devices?

The research area of antimicrobial surface coatings really started to take off around 2000, So the idea of incorporating antimicrobials onto the surface of medical devices is not a new one.

With more than 16 years’ research now, only a handful of products have made it into the clinic with the goal of saving lives by combating infectious agents that colonize surfaces. Their usage is not very wide-spread. But why is this so?

It is helpful to take as an example the most well-known antimicrobial products which are based on silver. One criticism is that the antimicrobial mechanism of silver is very broad — based on electrostatic interactions — and there is potential for interference with the biochemical machinery not only for pathogens but also for host cells. This idea of selectivity (harming only pathogens and not host cells) is exactly why when you go to a doctor to fight a nasty bacterial infection, you get an effective and approved antibiotic drug, and not a glass of silver nanoparticles.

So surfaces that incorporate antibiotic drugs may be promising for their ability to kill or inhibit microbial colonisation and have a well-known window of safety approved for their use.

Our latest publication on this topic is a mini-review called “Anti-infective Surface Coatings: Design and Therapeutic Promise against Device-Associated Infections”. Published in the open access journal PLOS Pathogens, the review is called a Pearl (i.e. “pearls of wisdom”) following the editorial guidance that it should be a “lesson that lasts”.

Our “Pearl” gets to the promises and pitfalls, as seen in a few literature examples, of how to best interface antibiotic surface coatings with pathogens. While there have been some innovative solutions, we are still a long way off from developing implantable devices that are both effective and compatible with the host. Will this take another 16 years until we see such devices enter the market? Probably not. An acceleration is taking place with nearly one paper published every day on the broad topic. We point out that the nexus between promise and pitfall is likely to narrow with a greater emphasis on collaboration between materials scientists, microbiologists, and clinicians. Indeed, in our own work, as can be seen by the co-authors on the paper, assembling a team with interdisciplinary skill sets is likely to create advances in this area.

Citation:

Coad BR, Griesser HJ, Peleg AY, Traven A (2016) Anti-infective Surface Coatings: Design and Therapeutic Promise against Device-Associated Infections. PLoS Pathog 12(6): e1005598. doi:10.1371/journal.ppat.1005598

http://journals.plos.org/plospathogens/article?id=info:doi/10.1371/journal.ppat.1005598

Important factors in the design of anti-infective materials and their surface coatings.

New bacteriostatic surfaces that release nitric oxide

Graphical abstract: Nitric oxide releasing plasma polymer coating with bacteriostatic properties and no cytotoxic side effects

Plasma polymerized coatings that release nitric oxide are compatible with human cells and have a bacteriostatic property. Image (C) Royal Society of Chemistry.

Nitric oxide (NO) plays an incredibly important role in biology which is just beginning to be understood.  From pulmonary dilation to wound healing, nitric-oxide based medical therapies are a huge and growing sector of human health.

A further aspect is NO’s ability to interfere with bacterial biofilm formation on surfaces. This opens up the way for new surface coatings that can release NO to stop infections from taking hold on medical devices.  A particularly challenging problem, however, is how to easily make surface coatings that store this reactive gas molecule. Furthermore, how can one make such a device containing a volatile, reactive molecule that has a long shelf-life?

Our new publication in Chemical Communications by Thomas Michl and Hans Griesser from the Mawson Institute, University of South Australia shows a method by which coatings that release NO can be deposited on virtually any substrate material.  Instead of volatile NO being trapped in the material, the surface coating contains a stable precursor of NO (an polymer containing a nitrosooxy group) that releases NO when exposed to solutions. Materials that were stored on the shelf for up to 2 months retained a bacteriostatic ability showing promise for their anti-biofilm ability. Importantly, when exposed to human stem cells, good compatibility was demonstrated showing that the material coatings were selectively bacteriostatic while being well tolerated by human cells.

The ability to deposit onto a range of different materials used in the medical industry as well as very good shelf life shows great promise for fabricating advanced medical devices with bacteriostatic properties.

Link to article:

Nitric oxide releasing plasma polymer coating with bacteriostatic properties and no cytotoxic side effects

New Publication in Microbiology Australia

What is the role of surface chemistry and materials science in combating fungal disease?

In my article in Microbiology Australia, I give my perspective on how scientists are transforming surface interfaces into active surfaces through nano-scale surface modifications: On the surface of it: the role of materials science in developing antifungal therapies and diagnostics.

Current Challenges in the Design of Effective Antifungal Surfaces (Poster)

Poster_image_lores

(Work is copyright Bryan Coad, 2014)

I presented this poster at the Australasian Society for Infectious Diseases (ASID) conference earlier this year.

I’m making it available for download for personal/educational use.

Clicking here will link to a PDF download (2 MB) of the full sized poster. The poster is copyrighted and not for reproduction. If you intend to use this work for personal/educational use, please contact me and I will provide a non-watermarked PDF copy.

Further Investigations of Gradient Polymer Brush Surfaces — New Publication

We have just published another study on polymer brush gradients in Langmuir.

Polymer Brush Gradients Grafted from Plasma-Polymerized Surfaces

Gradient polymer brush

Published in: Bryan R. Coad; Tugba Bilgic; Harm-Anton Klok; Langmuir  Article ASAP DOI: 10.1021/la501380m Copyright © 2014 American Chemical Society

This work describes a 3 step method for grafting polymer brushes from any substrate. Subsequent work (which happened to be accepted and published first) shows a 2 step method (see post here).

These two works show good understanding of different systems.  First, two different plasma polymer gradients were fabricated based on octadiene/allylamine and ethanol/ethylisobromobutyrate, and polymer grafting was shown for hydroxyethyl methacrylate (HEMA), dimethyl acrylamide (DMA), and poly(ethyleneglycol) methacrylate (PEGMA).  Last, we have show in this work gradient brushes grown from silicon wafers, and previously, from plastic coverslips.

I was especially pleased with this work as it gave me an opportunity to work with Prof. Harm-Anton Klok from EPFL in Switzerland.  Prof. Klok’s work was an inspiration for me during my PhD and I am very glad to have the chance to work with him in a nice collaboration.

Many thanks goes to him and his student, Tugba Bilgic, for helping me with this work.