A recent article on “Agents that Prevent Biofilm Formation” captured my interest[1]. The authors reviewed the literature and mentioned many substances which have shown in-vitro efficacy in disrupting biofilm production by the main offenders, i.e., S. aureus, S. epidermidis, P. aeruginosa and K. pneumoniae.
These substances come with very diverse chemical structures, some are clearly chaotropic agents disturbing the biofilm lattice, others interfere with the bacterial process of biofilm production itself.
There is no doubt that biofilm impacts on antibiotic efficacy in a major way. Biofilms are not only creating a barrier for antibiotic penetration, biofilm bacteria also have a different ‘life style’, more geared towards slow reproduction[2]. On wound surfaces and any kind of ‘hardware’, these infections are notoriously hard to cure. Even very high local concentrations of aminoglycosides several fold above MIC90 are unable to eradicate S. epidermidis in prosthetic joint infections (gentamicin impregnated cement) or P. aeruginosa in cystic fibrosis patients (after aerosol delivery).
A look at Clinicaltrials.gov with the search term ‘biofilm’ generated a hefty list of 40 trials. Well, this is an interesting bunch: dental plaque studies, topical treatments (burns) with various substances, studies in support of basic science (histology, immunology, microbiology), for diagnostics or for new materials are on this list but not even 1 (one) biofilm inhibitor is currently being tested for systemic use in systemic infections.
For topical use, a study in diabetic foot ulcers is listed as enrolling, comparing an iodine gel with standard dressing. The most interesting trial was unfortunately withdrawn because of ‘production issues’[3].
You will be glad to learn that quite a few studies are underway on how best to disrupt denture plaques. A long finished study on a drug-eluting ureteral stent remains without update or publication since 2013, another example of the many ‘orphan’ studies in this repository[4].
Well, it seems it is still early days for the anti-biofilm group of agents. With so many substances identified, some companies will eventually get lucky. The prospect of re-purposing antibiotics, of preventing of catheter-related (CLSI) and prosthetic device-related infections should be a major incentive for industry.
So far, Big Pharma is just standing on the sidelines while small VC companies are dedicating themselves to the cause. Agile Sciences, Arietis Pharmaceuticals (clpP activators), Cellceutix (brilacidin defensin mimetic), Contrafect (CF-301), Kane BioTech, N8 Medical (ceragenins), Polymer Therapeutics, Sarepta Therapeutics (PPMO technology) and many, many others are pushing forward; there will be a lot more visibility for the concept once PoC has been established for a compound.
This may well usher into a new and very exciting era of anti-infectives development.
For an up-to-date list of compound classes please refer to the reference articles listed below [1},{5].
References:
[1] N Rabin. Future Med. Chem. 2015; 7: 647
[2] K. Rumbaugh (ed) Antibiofilm Agents: From Diagnosis to Treatment to Prevention. Springer, 2014
[3] https://clinicaltrials.gov/ct2/show/NCT01646502?term=biofilm&rank=4
[4] https://clinicaltrials.gov/ct2/show/NCT00250406?term=biofilm&rank=26
[5] F Sun. Future Microbiol. 2013; 8: 877
