No abstract

Advances in nanotechnology have seen the development of several microbiocidal nanoparticles displaying activity against biofilms. These applications benefit from one or more combinations of the nanoparticle properties. Nanoparticles may indeed concentrate drugs on their surface resulting in polyvalent effects and improved efficacy to fight against bacteria. Nanodiamonds (NDs) are among the most promising new materials for biomedical applications. We elucidate in this paper the effect of menthol modified nanodiamond (ND-menthol) particles on bacterial viability against Grampositive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. We show that while ND-menthol particles are non-toxic to both pathogens, they show significant antibiofilm activity. The presence of ND-menthol particles reduces biofilm formation more efficiently than free menthol, unmodified oxidized NDs and ampicillin, a commonly used antibiotic. Our findings might be thus a step forward towards the development of alternative non antibiotic based strategies targeting bacterial infections.

Diamond nanoparticles (NDs) have demonstrated great promise as useful materials in a variety of biomedical settings. In this paper, the antimicrobial and antibiofilm activities of variously functionalized NDs against two common bacterial targets Gram‐negative bacterium Escherichia coli and Gram‐positive bacterium Staphylococcus aureus are compared. Hydroxylated (ND‐OH), aminated (ND‐NH2), carboxylated (ND‐COOH), mannose (ND‐Mannose), tri‐thiomannoside (ND‐Man3), or tri‐thiolactoside (ND‐Lac3)‐modified NDs are fabricated and evaluated in the present work. Of these, the mannose‐modified NDs are found to interfere most strongly with the survival of S. aureus, but not to influence the growth of E. coli. In contrast, particles featuring lactosyl units have the opposite effect on S. aureus growth. Sugar‐functionalized NPs reported to display antibacterial effects are rare. Only ND‐COOH particles are seen to have any effect on the growth profile of E. coli, but the effects are moderate. On the other hand, both ND‐NH2 and ND‐COOH are found to inhibit E. coli‐induced biofilm formation at levels comparable to the known E. coli biofilm disruptor, ampicillin (albeit at concentrations of 100 μg mL−1). However, none of the modified particles examined here reveal any significant activity as disruptors of S. aureus‐induced biofilm formation even at the highest concentrations studied.

The role of molecular arrangement of hydrophobic and hydrophilic groups for designing membrane-active molecules remains largely ambiguous. To explore this aspect, herein we report a series of membrane-active small molecules by varying the spatial distribution of hydrophobic groups. The two terminal amino groups of linear triamines such as diethylene triamine, bis­(trimethylene)­triamine, and bis­(hexamethylene)­triamine were conjugated with cationic amino acids bearing variable side chain hydrophobicity (such as diaminobutyric acid, ornithine, and lysine). The hydrophobicity was also modulated through conjugation of different long chain fatty acids with the central secondary amino group of the triamine. Molecules with constant backbone hydrophobicity displayed an enhanced antibacterial activity and decreased hemolytic activity upon increasing the side chain hydrophobicity of amino acids. On the other hand, increased hydrophobicity in the backbone introduced a slight hemolytic activity but a higher increment in antibacterial activity, resulting in better selective antibacterial compounds. The optimized lead compound derived from structure–activity-relationship (SAR) studies was the dodecanoyl analogue of a lysine series of compounds consisting of bis­(hexamethylene)­triamine as the backbone. This compound was active against various Gram-positive and Gram-negative bacteria at a low concentration (MIC ranged between 3.1 and 6.3 μg/mL) and displayed low toxicity toward mammalian cells (HC50 = 890 μg/mL and EC50 against HEK = 85 μg/mL). Additionally, it was able to kill metabolically inactive bacterial cells and eradicate preformed biofilms of MRSA. This compound showed excellent activity in a mouse model of skin infection with reduction of ∼4 log MRSA burden at 40 mg/kg dose without any sign of skin toxicity even at 200 mg/kg. More importantly, it revealed potent efficacy in an ex vivo model of human skin infection (with reduction of 85% MRSA burden at 50 μg/mL), which indicates great potential of the compound as an antibacterial agent to treat skin infections.

Aims This paper presents the potential of environmentally sourced bacteriophages to affect the growth of clinical isolates of Pseudomonas aeruginosa biofilms, and assesses the respective plaque morphotypes presented by each bacteriophage, in vitro. Methods and Results Bacterial host strains were typed for their ability to produce the quorum sensing‐controlled virulence factor pyocyanin, and then tested for bacteriophage susceptibility using the spot test method. The bacteriophages were co‐administered with ciprofloxacin in order to determine whether the bacteriophages would demonstrate synergistic or antagonistic behaviour to the antibiotic in vitro. Results suggest a potential relationship between the bacteriophage plaque size and biofilm inhibition, where those producing smaller plaques appear to be more effective at reducing bacterial biofilm formation. Conclusions This phenomenon may be explained by a high adsorption rate leading to the rapid formation of smaller plaques, and greater biofilm reduction associated with the loss of viable bacterial cells before the cells can adhere to the surface and form a biofilm. Results from the co‐administration of bacteriophage and ciprofloxacin suggest that the two work synergistically to affect P. aeruginosa biofilms. Significance and Impact of the Study The data indicate enhanced efficacy of ciprofloxacin by ≥50%. This could offer an alternative strategy for targeting antibiotic‐resistant infections.

The opportunistic pathogen Pseudomonas aeruginosa is a significant contributor to recalcitrant multi-drug resistant infections. In a vigorous search for alternative therapeutic approaches, the communication system used by this bacterium to synchronise the expression of genes involved in pathogenicity has been identified as a potential target. Poly(ε-lysine) dendrons, composed of three branching generations, were examined herein for their anti-virulence potential and ability to disperse within P. a eruginosa biofilms. These hyperbranched macromolecules reduced attachment and biomass production under different nutrient growth conditions, and at concentrations that were not lethal to planktonic cells (0.2, 0.4 and 0.8 mg/mL). Fluorescent labelling revealed the intracellular localisation and cell-penetrating capacity of the dendron, and showed the rapid uptake and release of unexploited dendron from pre-established P. a eruginosa biofilms. Additionally, the dendron induced complete attenuation of LasA protease, a marker of quorum sensing inactivation, by preventing its accumulation in the external environment. This study thus demonstrates the anti-virulence potential of this class of macromolecules, and could represent a novel therapeutic approach for the treatment of antibiotic-resistant P. a eruginosa infections.

Human lung organoids (HLOs) are increasingly used to model development and infectious diseases, however their ability to recapitulate functional pulmonary tissue response to nanomaterials (NMs) has yet to be demonstrated. Here, we established a lung organoid exposure model that utilises microinjection to present NMs into the lumen of organoids. Our model assures efficient, reproducible and controllable exposure of the apical pulmonary epithelium, emulating real-life human exposure scenario. By comparing the impact of two well studied carbon-based NMs, graphene oxide sheets (GO) and multi-walled carbon nanotubes (MWCNT), we validated lung organoids as tools for predicting pulmonary NM-driven responses. In agreement with established in vivo data, we demonstrate that MWCNT, but not GO, elicit adverse effects on lung organoids, leading to a pro-fibrotic phenotype. Our findings reveal the capacity and suitability of HLOs for hazard assessment of NMs, aligned with the much sought-out 3Rs (animal research replacement, reduction, refinement) framework.

The antibacterial and antibiofilm properties of diamond nanoparticles are shown by A. Siriwardena, P. J. Cragg, S. Szunerits, and co‐workers to be both bacterium‐ and ligand‐dependent. On page 822, S. aureus‐induced biofilm inhibition is observed for ND‐NH2, ND‐COOH, and ND‐OH particles, but proves only moderate even at the highest particle concentrations tested. ND‐NH2 and ND‐COOH, however, are found to inhibit E. coli‐induced biofilm formation at levels comparable to the known E. coli biofilm disruptor, ampicillin.