"We realised this was a way to resurrect antibiotics that bacteria have become resistant to," says Vincent Rotello, professor at the University of Massachusetts at Amherst. Retrieving the efficacy of these drugs has great benefits over attempts to just use antibacterial nanomaterials instead on account of the specificity of drugs.

Nanomaterials tend to lyse cell membranes indiscriminately. While there has been some recent progress in tuning nanomaterial systems to preferentially kill bacterial versus mammalian cells, the action of drugs is inherently specific because they target "specific" pathways. Rotello and his team had been looking for a way of improving the specificity of the microbial action of nanoparticles by combining them with drugs, and instead found that the nanoparticles shut down altogether the main strategy bacteria use to resist drug action. Using the two together could prevent the development of bacterial resistance and improve the efficacy of drugs by up to a factor of 16.

"Being chemists not medicinal types – I think it took us a little while to realise how important even a fourfold increase is," says Rotello. "You don't tend to think of dosing as how much material you have to put in the body, but 16 times less is the difference between eating it like cereal and eating a pill." The main strategy that bacteria adopt to resist drug action is to simply kick the chemicals out of the cell through what is known as the bacterial efflux pump. There have been efforts to develop drugs to circumvent this efflux action chemically, but the bacteria find ways to counter it. Instead the nanoparticles just block the efflux action altogether.

"Bacteria are really good at taking the tools they have and tweaking them," says Rotello. "But the pump has evolved over billions of years – it's not quick for them to come up with a totally different mechanism."

The nanoparticles also support the antibacterial activity of drugs in other ways. "Transporter proteins crucial for the survival of the bacteria are also repressed, which helps the antibiotics to work more effectively," adds Akash Gupta, a graduate student in Rotello's lab and first author of the paper reporting the results, the first report of this kind of mechanism for nanomaterial antibacterial activity.

Hydrophobic ligands

The researchers looked at the minimum concentration of drugs – including levofloxacin and ciprofloxacin – needed to inhibit E. coli with and without gold nanoparticles. In previous work the researchers had identified that the surface chemistry of 2 nm gold nanoparticles influenced the way they interact with bacteria. Akash tells nanotechweb.org that in particular hydrophobic ligands were found to bind to the bacteria very effectively.

Cell membranes themselves are hydrophobic so their disruption when hydrophobic elements are added is perhaps no surprise, but the challenge is getting the hydrophobic ligands to interact with the bacteria and not each other. As Rotello tells nanotechweb.org: "hydrophobic things love each other", which means they tend to bundle in on themselves. Here, attaching them to a nanoparticle works wonders as the nanoparticle itself gets in the way of their introvert tendencies. With the ligands a little more open there is a greater possibility to lock in with the hydrophobic cell membrane instead of just themselves, allowing the nanoparticle antibacterial action to take effect.

Cyborg futures

Despite the advances made in understanding both the use of drugs against infection and the potential of nanomaterials, there has been little previous work on a potential synergy between the two approaches. Certainly the skills and lab requirements for studies that straddle both advanced drug and nanoparticle investigations are far from trivial. However, Rotello suggests there may be additional reluctance from the drug community to embrace nanoparticle research on account of the well entrenched methodologies in use and a certain distrust of nanomaterials. On the other hand the nanomaterial community can be prone to trust that nanomaterials can solve everything so that there is no need for an alliance with incumbent techniques.

Akash has already begun work applying the nanomaterial drug combination in vivo and they are confident of the potential of the approach based on the results achieved so far. In addition nanoparticles are generally classed as devices because their action is general, and the drugs they hope to "resurrect" have already previously passed clinical trials. As a result progress from the lab to the bedside may be more rapid than the ten-year or so delay usually expected to complete clinical trials.

"It’s the cyborg approach to therapeutics," says Rotello. "Taking the man-made and the biological, bringing them together and not having them work as a+b = a+b but a+b = x, and this is an area that is rapidly emerging."

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