Robust Antibacterial Activity of Tungsten Oxide (WO3-X) Nanodots
Preprint posted on December 13, 2018 https://www.biorxiv.org/content/early/2018/12/13/494260
Background of preprint
Inorganic nanomaterials exhibit distinctive properties owing to their small size, large surface area, and high reactivity. These special features make inorganic nanomaterials highly applicable to various biomedical fields: biocatalysis, cell imaging, drug delivery, tumour diagnosis and treatment, and as antibacterial agents. Unfortunately, many inorganic nanomaterials are toxic to mammalian cells, which have hindered the clinical progress of these inorganic nanomaterials as useful antibiotics despite their potent antibacterial properties. In their preprint, Duan et al. explored the antibacterial properties of ultrasmall WO3-x nanodots that were previously synthesised in their previous paper .
Key findings of preprint
Following their previously published procedure , Duan et al. first synthesised uniform and ultra-small WO3-x nanodots. This was especially important because smaller particles had more potent antibacterial properties than larger particles, a phenomenon attributed to better penetration of bacterial cell walls and enhanced interaction of such membranes. The authors’ subsequent findings can be categorised into two parts: the antibacterial activity of WO3-X nanodots, and the toxicity of these nanodots to mammalian cells.
Antibacterial activity of WO3-X nanodots. Using a standard colony counting assay based on Escherichia coli and Staphylococcus aureus, Duan et al. found that WO3-x killed bacterial in both a time- and concentration-dependent manner. Interestingly, the gram-positive S. aureus was more sensitive to WO3-X than the gram-negative E. coli. The preprint authors attributed the difference between the sensitivities of S. aureus and E. coli to differences in structures of cell walls and membranes—the additional outer membrane present in gram-negative E. coli but not in gram-positive S. aureus may have acted as an additional physical layer that conferred greater resistance of E. coli to the WO3-X nanodots.
Having established that the WO3-X nanoparticles indeed had antibacterial activity, Duan et al. then investigated the mechanisms by which WO3-X nanoparticles killed the bacteria. Two experiments were used to determine this: first, the morphology of bacterial membranes was measured using Scanning Electron Microscopy (SEM) and Tunnelling Electron Microscopy (TEM); and second, molecular dynamics (MD) simulations were performed to understand how WO3-X nanoparticles accumulate near the membrane.
SEM revealed that the WO3-X nanoparticles deposited onto bacterial cell surfaces within 2 h, causing them to deform: E. coli cells became coarse and potholed, while S. aureus cells lost their cytoplasm and collapsed. The TEM images served to reinforce the implication that the direct interaction between the WO3-X nanodots and the bacterial membranes caused the disruption of bacterial membrane function. Following the MD simulations, the authors demonstrated that the WO3-X nanoparticles do not serve to disrupt the membrane by extracting lipid molecules; instead, the interaction with the lipid head groups served to aid adsorption onto the membrane surface. In turn, this adsorption enabled WO3-X nanodots to interfere with the functions of membrane and membrane proteins, as well as enhance the reactivity of reactive oxygen species (ROS). Specifically, Duan et al. measured the photoinduced ROS generation ability of WO3-X using electron spin resonance (ESR) spectroscopy, demonstrating that WO3-X was capable of generating the hydroxyl radicals ·OH under irradiation of sunlight. The preprint authors posit that the reaction of these hydroxyl radicals with water may be responsible for WO3-X antibacterial activity.
Biocompatibility and cytotoxicity to mammalian cells. By testing the cytotoxicity of WO3-X nanodots on human bronchial epithelial cell line (Beas-2B) and human umbilical vein endothelial cell (HUVEC), Duan et al. showed that WO3-X was unlikely to be toxic to mammalian cells. Because nanoparticles are notorious for their cytotoxicity, such a series of experiments is essential in the further development of WO3-X as an antibiotic. The authors found that even when these mammalian cells were exposed to significantly higher concentrations of WO3-X than those effective for antibacterial activity, cell viability was largely preserved. Moreover, HUVEC and Beas-2B were also not sensitive to the photocatalytic effect of WO3-X; this was attributed to the presence of auto-antioxidant systems in mammalian cells which protected them from the ROS generated from the irradiation of simulated sunlight.
What I like about this preprint
In highlighting the potential of WO3-X nanodots as antibacterial agents in treating S. aureus and E. coli infections, Duan et al. hope that their discovery will lead to the eventual development of drugs that can be used to treat infections caused by multidrug resistance that they discussed in their introduction. This is especially interesting to me because nanoparticles are a very new technology, that, perhaps somewhat paradoxically, has been around for almost a decade now. The very factors that lend themselves to the unique efficacy of nanoparticles are also responsible for their intractability in manufacturing, quality control, and even safety. Despite the extensive research that has gone into characterising nanoparticle behaviour, the majority of theories about nanoparticle behaviour remains controversial . Therefore, more sophisticated nanoparticle designs or formulations are needed to make them more amenable to being used as potential drug treatments. Through their preprint, Duan et al. share preliminary research that will be useful in informing future research into the development of metal oxide nanoparticles as antibacterial agents.
In this final section of my preLight, I briefly discuss the remaining research ahead by classifying it into two categories. First, the in vivo and in-human efficacies of WO3-X must be proven in a series of preclinical studies and clinical trials, because the effectiveness of WO3-X nanoparticles is also affected by other factors, such as its pharmacokinetics. Second, further in vivo and in vitro cytotoxicity testing must be conducted before these nanodots can be used to treat infections in humans. Because nanoparticles are a nascent technology, a better understanding of the potential toxicities of these antibacterial agents will be needed before approval is granted in the use of these nanodots as systemic antibiotics. After all, the use of any antibiotics must advantage more than do patients wrong.
Questions for authors
- Why were the human bronchial epithelial cell line (Beas-2B) and human umbilical vein endothelial cell line (HUVEC) chosen to test for the cytotoxicity of these WO3-X nanodots? What about other cell lines that are also commonly chosen, such as HepG2 or HEK293, to test for liver and kidney toxicity respectively?
- Why were aureus and E. coli selected to test for the efficacy of WO3-X nanodots? Were other more pathogenic bacteria or strains, such as methicillin-resistant S. aureus tested?
- Similarly, how effective are WO3-X nanodots against mycobacteria, which are known to be highly resistant to most drugs due to their cell walls?
- How effective are these nanodots likely to function as antivirals? Some viruses have been postulated to disrupt the endogenous antioxidant pathways of mammalian cells. Do you predict that these nanodots are therefore likely to be selective for these infected cells?
 Wen L, Chen L, Zheng S, Zeng J, Duan G, Wang Y, Wang G, Chai Z, Li Z, Gao M, Ultrasmall Biocompatible WO3−x Nanodots for Multi-Modality Imaging and Combined Therapy of Cancers, Advanced Materials 28(25) (2016) 5072-5079.
 Danhier F, To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine?, Journal of Controlled Release 244 (2016) 108-121.
Posted on: 21st December 2018Read preprint
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