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The quest to develop novel methods to combat drug-resistant and infectious diseases such as Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE), which continue to pose serious challenges to human health worldwide due to the inherent ability of the disease-causing microbes to develop antibiotic resistance, has been spurring innovative research into the medical applications of nanotechnology in recent years.

One of the most remarkable achievements in the rapidly growing field of nanomedicine has been the successful synthesis of the first biodegradable polymer-based nanoparticle capable of combating multidrug-resistant microbes, which works by selectively targeting and tearing down bacterial cell walls and membranes. Designed by researchers at the A*STAR Institute of Bioengineering and Nanotechnology (IBN) and the IBM Almaden Research Center, the unique nanoparticle has been featured as one of Scientific American’s top ten world changing ideas.

Referring to the novel design as a ‘nanotech knife’, as a way of describing the lethally effective, precise nature of the technology, Scientific American has featured the work conducted by the team of A*STAR and IBM researchers in its special end-of-year report, ‘World Changing Ideas — 10 New Technologies That Will Make a Difference’ published in its December 2011 issue.

 “We are delighted that Scientific American recognizes our nanoparticle discovery as a world changing idea,” says Jackie Y. Ying, IBN’s executive director. “This is an excellent affirmation of our nanotechnology research against drug-resistant bacteria and we will now be focusing on developing these nanoparticles for clinical and consumer applications.”

A new way to fight disease

Antibiotics traditionally work on the principle of using chemical compounds to act on specific molecular targets within bacteria, which leads to therapeutic specificity but allows resistance development through mutation. In contrast, the bacteria-killing nanoparticle developed by the IBN research team and colleagues at IBM may help to circumvent many of the problems associated with conventional methods of antibiotic therapy by utterly disintegrating the bacteria’s physical structure at the outset. This novel methodology has therefore been garnering widespread interest due to the way in which it offers a fundamentally different approach to fighting disease.

The nanoparticles begin their assault on harmful bacteria by forming cationic (positively charged) clusters that are drawn towards the anionic (negatively charged) bacterial cell membranes. By selectively binding to the bacterial cell membranes in this way, the nanoparticles avoid harming human cell membranes, leaving red blood cells, for example, intact. After targeting, puncturing and destabilizing the bacterial cell wall, the nanoparticles eventually break down and kill the bacterial cell. The physical destruction of the bacterial cell membrane can delay or eliminate resistance development. (See Nanomedicine: Germ killers).

Using transmission electron microscopy, the IBN research team led by Yiyan Yang observed the extent of damage inflicted by the nanoparticles on the bacterial cell walls and membranes, and was thus able to confirm that selective cell lysis had been achieved.

“We hypothesize that the cationic nanoparticles could interact easily with the negatively charged cell wall by means of an electrostatic interaction, and the steric hindrance imposed by the mass of nanoparticles in the cell wall and the hydrogen-binding/electrostatic interaction between the cationic nanoparticle and the cell wall may inhibit cell wall synthesis and/or damage the cell wall, resulting in cell lysis,” says Yang. “In addition, the nanoparticles may destabilize the cell membrane as a result of electroporation and/or the sinking raft model, leading to cell death. The nanoparticles damaged the cell wall and cell membrane like a ‘knife’.”

The team discovered that the nanoparticles could efficiently kill Gram-positive bacteria, MRSA and fungi, even at low concentrations. The nanoparticles showed no significant activity against red blood cells, and no obvious acute toxicity was observed during in vivo studies in mice, even at concentrations well above their effective dose.

The nanoparticles themselves are easily broken down by enzymes in the human body as they are composed of biodegradable polymers. Whereas most antimicrobial polymers developed to date have been non-biodegradable, which render difficulty in obtaining regulatory approval, the new nanoparticles offer a significant step forward for in vivo clinical trials. In addition, the biodegradable nanoparticles can be produced in large quantities and at low cost.

Future applications

Among the many future applications envisioned by the IBN research team is the development of nanoparticle-infused gels that could be easily applied to treat skin infections, or developing ways to inject the nanoparticles into the patients’ bloodstream directly.

“As these nanoparticles can kill drug-resistant bacteria such as MRSA and fungi, they may be used to treat MRSA-induced skin or blood stream infections,” says Yang. “They may also be used in mouthwash and deodorant formulations, and as a preservative.”

As MRSA has been of particular concern in hospitals and other healthcare settings such as nursing homes and dialysis centers, where patients with open wounds or weakened immune systems are more susceptible to infection, measures to ensure that high hygiene standards are maintained are of vital importance. Patients are often advised to wash their hands before and after eating a meal, and many hospitals now routinely offer hand wipes to help prevent the spread of MSRA.

The nanoparticles could also greatly help to prevent the spread of infection before and after surgery. “Doctors could apply the nanoparticle-infused gels or lotions on their hands prior to surgical operations to prevent post-surgery infection. Nurses could also use the gels or lotions on their hands to prevent bacteria transfer from one patient to another. The nanoparticle-infused sprays may be used to sterilize the surfaces of furniture and equipment in hospitals to kill bacteria,” says Yang.

Since its establishment in 2003, the IBN has been rapidly building a reputation as a world-class hub for bioengineering and nanotechnology. By providing a research environment that links multiple disciplines and playing an active role in partnering with global institutions, the IBN is developing new technologies, biomaterials, devices, systems and processes to produce research breakthroughs aimed at improving healthcare and quality of life.