Bacterial
biofilms are surface-attached communities of microorganisms; protected from
external assault by an extracellular matrix of polysaccharide, protein and
nucleic acids. When in this biofilm state, bacteria are significantly more
resistant to antibiotics and have utilized this line of defense to infiltrate
every environment, including the human body. This is of particular concern as it
is estimated that up to 80% of all microbial infections are biofilm based. A
prominent problem is the Biofilm infections of indwelling medical devices i.e.
catheters, as the infections are almost impossible to eradicate.
In
order to find anti-biofilm agents, natural products have been extracted from
marine organisms. Sponges have been found to possess anti-biofilm properties,
however only two classes of sponge metabolites have been found to possess
non-bactericidal biofilm modulators: the terpenoids and the pyrrole-imidazoles.
Because of this, there is now an increased effort towards the development of
small synthetic molecules that will inhibit and/or disperse bacterial biofilms.
Stowe
et al. (2011) give a very descriptive account on biofilm formation and the role
it plays in the natural phenomenon of biofouling. The paper discusses the
implications biofilm has on industry and medicine and the anti-biofilm agents that
are derived from marine sponges. These being: the terpenes and their
derivatives and the pyrrole-imidazole alkaloids (PIAs): oroidin, screptin and
bromoageliferin. These were extracted from several families of sponge, with a
particular focus of bromopyrrole derivatives from the Agelasidae family. Natural products PIAs have been found to be very
toxic agents and have microbicidal properties; working against microorganism
and higher organisms. Due to these properties, Stowe et al. looked to
synthesise from these natural molecules anti-biofilm compounds that were non-microbicidal.
Stowe
et al. were able to develop several successful anti-biofilm compounds that had
non-microbicidal properties. In particular, two bromoageliferin derivatives: trans-bromoageliferin (TAGE) and cis-bromoageliferin (CAGE). The
compounds were tested for anti-biofilm activity against Pseudomonas aeruginosa using crystal violet assays. They were found
to inhibit biofilm formation. To support TAGE’s role as a non-microbicidal
biofilm modulator, fluorescence-based experiments with confocal laser scanning
microscopy (CLSM) and flow cytometry were used to visualize the phenotypic
effects of the molecule. CLSM demonstrated that 100 μM
TAGE affected the biofilm structure of P.
aeruginosa.
Stowe et al. then combined these anti-biofilm compounds with
conventional antibiotics and found that the results of which, resensitized
previously resistant bacterial strains; this allowed the commercial drug to
resume activity. In particular the combination of the compound and antibiotic
were able to resensitize drug-resistant methicillin-resistant Straphylococcus aureus (MRSA) and
multi-drug resistant Acinetobacter
baumannii (MDRAB).
These “Helper Drugs” derived from marine sponges will most likely
act as adjuvants to conventional antibiotics against antibiotic resistance.
However, toxicity tests must be carried out to establish the effect these
anti-biofilm compounds have on bacteria in their native host, for example: gut
bacteria, before they can be tested on animal models and developed for
medicinal use. I chose to review this article because the results obtained have
contributed significantly to our knowledge of bacteria bio-film structure and
offered promising solutions to the current anti-biotic resistance crisis.
'Anti-Biofilm Compounds Derived from Marine Sponges', Marine Drugs, 9, 2010-2035.
http://www.mdpi.com/1660-3397/9/10/2010
Hi Carys, I was really interested in your post so had a quick look over the paper you reviewed. The first thing I noticed was a lack of normal paper layout with no formal method or results section and then I realised the paper is like a review article which included primary work by the authors, do you know if they have published their results anywhere else including more detail?
ReplyDeleteAnyway, the reason I read over it was to look for information on the pathways and mechanisms of the different anti-biofilm compounds you mentioned; I’m interested in how they actually work. I found some information on the mode of action of Manoalides. These compounds work by quorum sensing inhibition (QSI), where bacterial attachment is prevented by blocking communication amongst bacteria. It therefore makes sense this is a non-microbicidal mechanism. I couldn’t find much information in the paper about the pathway of bromoageliferin.
I personally haven’t read much around this topic so please forgive my unawareness; I was just wondering how well the scientific community understand the pathways of these compounds? If it is unknown then surely characterizing the pathways should be an important research initiative before this goes to medical trial?
Hi Carys, this is a very important development for the medical industry, as well as industries such as shipping and many others that rely heavily on equipment that are effected by bacterial biofilm formation, which frankly can be anything due to bacterias ability to form biofilms on a variety of surfaces from metals to human cells, as you mentioned above.
ReplyDeleteI read into biofilms and how the bacteria within are effected and came up with what i thought would be an interesting area to investigate further.
Biofilms, once formed, are difficult to remove. There a several theories surrounding this including an increased difficulty in antibiotics diffusing into biofilm; therefore not being able to act on the cells of the bacteria in question (Williamson et al. 2012). Also gene expression can be altered amongst the bacteria in a biofilm due to quorum sensing, which results in a different phenotype being expressed (Behkne et al. 2011). These have been termed ‘persister cells’ cells because they survive despite the surrounding cells being detached or damaged in some form.
This paper states that biofilm formation is prevented when the synthetic compound is introduced to Pseudomonas aeruginosa. It would be interesting to observe if this compound would also have an effect in removing biofilms as well as preventing, presuming that initially the bacteria are planktonic since they are not originally part of a biofilm, and therefore possibly exhibit a different phenotype to those that have formed a biofilm. Another point would be how far within the biofilm are these compounds able to penetrate to act on the necessary cells.
This is a really interesting review. Just a point on Megan's comment, from what I have read synthesised TAGE or trans-bromoageliferin will both stop biofilm formation and disperse biofilms which have already formed by directed affecting biofilm architecture (Huigens et al. 2008, Molecular Biosystems 4(6), 614-21). If any of you are interested in biofilm control, there is another new review out in Organic & Biomolecular Chemistry entitled ‘Small molecule control of bacterial biofilms’ by Roberta Worthington and colleagues.
ReplyDeleteHi Carys, I enjoyed this review as it has many potential uses in numerous industry's like Megan said, it would be interesting to see how this avenue of research unfolds in respects to medicine.
ReplyDeleteOne point I am slightly confused about is; after the formation of a biofilm by say MRSA for example, does the film protect the bacteria from certain compounds by the rejection of certain functional groups and their spacial arrangement or is it more complex? I ask because surely the films arent blocking the intercommunications between bacteria within the community (ie P.aeruginosa quorum sensing), so is it the size of chemicals it filters or would it be more specific? I dont know much in this field but it certainly is intriguing!