Thursday, 9 January 2014

New Type of Antifungal Drug: Low Toxicity/High Potential?

In common with many antimicrobial drugs, microbes resistant to antibiotic/antifungal drugs are being found with increasing regularity. This indicates that we must look for new drugs that are effective against microbial strains resistant to existing antimicrobials, and preferably we need drugs that microbes find very difficult to become resistant to.

New antifungal drugs have been produced regularly over the last 20 years and clinicians now have a lengthy list to choose from including; amphotericin, itraconazole, voriconazole, posaconazole, micafungin, anidulafungin and several more.

Resistance to these drugs is relatively widespread and one reason is that there are relatively few drug classes so drugs tend to be quite similar in structure and mode of action, so resistance mechanisms that defeat one drug in a class sometimes also defeat another in the same class. We need new types of antifungal drugs that form new classes!

The recent paper in Nature Communications suggests that progress has been made towards the development of a new type of drug, one that is efficient and pathogen specific (thus hopefully less toxic to the patient). Earlier work with Macromolecular antimicrobial agents such as cationic polymers and peptides has demonstrated that they can have antifungal properties and a markedly targetable against microbial cell membranes, thus leaving human cell membranes undamaged.

Self assembly of polymers
These tiny particles self assemble into highly active structures once they become dissolved in water and are biodegradable - making them highly attractive as medication as they will be eliminated from the patients body once their job is done.

Their mode of action is similar to that of amphotericin as they incorporate themselves into microbial cell membranes and form large pore-like structures, allowing the cell contents to escape - an assault that microbes find extremely difficult to resist or to develop resistance to - there is currently very little resistance to drugs based on amphotericin in clinics for example even after many years of use. Unlike amphotericin there seems to be much less tendency to attack human cell membranes, and we can easily dissolve these polymers in water (unlike amphotericin) so effectively we get all the advantages offered by amphotericin without the drawbacks of toxicity & irritant solvent. An added bonus is that these polymers are nanoparticles and capable of penetration into biological tissue & through inhibiting biofilms.

Successful testing of these new synthetic polymers (cheap to manufacture to large scale) is reported in the latest paper and has shown positive results both in vitro (in laboratory test dishes) and in vivo (in living animals) - with successful treatment of fungal keratitis (fungal eye infection) in a mouse model.

At the moment this type of drug depends on getting sufficient particles to the site of infection. This is far more difficult when giving as an injection or as oral medication so its use is restricted to sites we can directly reach (e.g. the eye) but now that the principle is established we can hope that this will change and we may see 'whole body' versions of these drugs in the future.

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