Final Report Summary - PHOTORELEASE (Fabrication of particles with photo receptors: bio-analytical application such as controlled drug delivery)
Bacterial infectious diseases pose a major threat to human health. Several share clinical characteristics such as chronic inflammation and tissue damage, and are greatly exacerbated when microorganisms grow as biofilms on mucosal surfaces or medical devices.Biofilms can be defined as communities of microorganisms interacting together with one another and/or with a surface and which are embedded in a self-produced extracellular matrix.The molecular constituents and complex architectures of biofilms enable the bacteria residing within them to counter and resist the action of the human immune system and to enhance their tolerance towards antibiotics, leading to infections that are very difficult to eradicate.The threat of biofilm-related infections has been greatly aggravated with the emergence of multidrug resistant bacteria, a phenomenon that has been compounded in the past decades with the overuse and misuse of antibiotics. These and other considerations have generated an increased interest in the development of non-biocidal anti-infective strategies as alternatives to antibiotics, as these would be expected to show reduced tendency to provoke the appearance of resistant strains. One such approach is the use of anti-adhesive molecules that target specifically the initial interaction of bacteria and surfaces that constitutes a critical step for effective colonization and establishment of biofilm by pathogens.
The race for the discovery of anti-infective molecules has recently benefited from advances in nanotechnology with the development of a number of microbiocidal and/or anti-adhesive nanoparticles displaying activity against biofilms. Under the different nanomaterials proposed, diamond nanoparticel (also termed nanodiamonds) have in particular drawn attention from the scientific community. Nanodiamonds are completely inert, optically transparent, biocompatible and moreover, easily functionalizable via a variety of strategies depending on their intended application.Although their in vivo toxicity depends in particular on their surface characteristics, ND particles have thus far been reported not to induce significant cytotoxicity in a variety of cell types. The EU funded "PHOTORELEASE" project took advantage of the interesting properties of nanodiamonds to develop novel inhibitors for E. coli based biofilm formation. This 1st-generation of sugar-conjugated nanodiamonds showed marked anti-adhesive activity in cell-based assays without displaying toxicity against eukaryotic cells. This conforted us in our choice of particle and convinced us that sugar-NDs should indeed be further pursued as promising biomaterials. We selected further trimeric mannoside clusters in which the sugar units are thioglycosides rather than the more typical O-glycoside-based ligands (such as those in our 1st-generation sugar-NDs). These ND-glycan inhibitors were found to be 30 times more active than the unconjugated sugar cluster and 3 times more active than the first generation of nanodiamond. Rather unexpectedly, the tri-thiomannoside cluster alone did displayed a relatively potent inhibition of biofilm formation, while the corresponding ND-conjugated tri-thiomannoside cluster gave only a four times greater relative inhibitory potency than when not conjugated. This result is unprecendented and might need to be considered further. Indeed, mannoside clusters in which the sugar units are thioglycosides rather than the more typical O-glycoside-based ligands have until now not been considered as inhibitors. Using a thioglycoside linkage renders the anomeric tethering function much more robust to acidic or enzymatic hydrolysis than the O-glycosidic functions making such structures of special interest for various applications.
The impact of such novel therapeutics to society cannot be underestimated. While not tested in vitro, such an appoach could have important consequences for the treatement of antibiotic-resistanc bacteria strains. Research on this topic will thus continue with the hope for improving health risks to society using engeneered therapeutics.
The race for the discovery of anti-infective molecules has recently benefited from advances in nanotechnology with the development of a number of microbiocidal and/or anti-adhesive nanoparticles displaying activity against biofilms. Under the different nanomaterials proposed, diamond nanoparticel (also termed nanodiamonds) have in particular drawn attention from the scientific community. Nanodiamonds are completely inert, optically transparent, biocompatible and moreover, easily functionalizable via a variety of strategies depending on their intended application.Although their in vivo toxicity depends in particular on their surface characteristics, ND particles have thus far been reported not to induce significant cytotoxicity in a variety of cell types. The EU funded "PHOTORELEASE" project took advantage of the interesting properties of nanodiamonds to develop novel inhibitors for E. coli based biofilm formation. This 1st-generation of sugar-conjugated nanodiamonds showed marked anti-adhesive activity in cell-based assays without displaying toxicity against eukaryotic cells. This conforted us in our choice of particle and convinced us that sugar-NDs should indeed be further pursued as promising biomaterials. We selected further trimeric mannoside clusters in which the sugar units are thioglycosides rather than the more typical O-glycoside-based ligands (such as those in our 1st-generation sugar-NDs). These ND-glycan inhibitors were found to be 30 times more active than the unconjugated sugar cluster and 3 times more active than the first generation of nanodiamond. Rather unexpectedly, the tri-thiomannoside cluster alone did displayed a relatively potent inhibition of biofilm formation, while the corresponding ND-conjugated tri-thiomannoside cluster gave only a four times greater relative inhibitory potency than when not conjugated. This result is unprecendented and might need to be considered further. Indeed, mannoside clusters in which the sugar units are thioglycosides rather than the more typical O-glycoside-based ligands have until now not been considered as inhibitors. Using a thioglycoside linkage renders the anomeric tethering function much more robust to acidic or enzymatic hydrolysis than the O-glycosidic functions making such structures of special interest for various applications.
The impact of such novel therapeutics to society cannot be underestimated. While not tested in vitro, such an appoach could have important consequences for the treatement of antibiotic-resistanc bacteria strains. Research on this topic will thus continue with the hope for improving health risks to society using engeneered therapeutics.
