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Bludgeoning bacteria instead of drugging it

The nanoparticles, which IBM says are relatively inexpensive, were effective against bugs that have been evolving to resist antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA). Preliminary results suggest the particles could also be effective against yeast, fungus and small bacteria like E. coli, IBM says. Research on the new particles is reported in this week’s issue of the journal Nature Chemistry.

Antibiotics kill microorganisms in various ways, including interfering with their DNA or interacting with their ability to rebuild their cell walls, explains James Hedrick, advanced organic materials scientist and master inventor at IBM Almaden Research Center in San Jose, Calif. But some of the bugs survive the onslaught, leading to new generations of bacteria that won’t succumb to the drugs.

A new class of positively charged plastic micro-machines, including IBM's nanoparticles, take a somewhat more physical approach.

“These are designed to slice the cell membrane, to rip the membrane up and eliminate the contents,” Hedrick said. “It’s kind of like the way a virus would work — a virus drills a pore, empties the contents and hijacks it. This is drilling in little holes, and all the contents leak out.”

Transmission electron micrographs show it works: As the images show, the cell walls have been ruptured and everything inside is gone. The best part is that bacteria cannot evolve resistance because it's a physical attack, not a chemical one.

These particles are special because they self-assemble in water and are biodegradable, unlike other nanoparticle treatments. They’re made of amphiphilic polycarbonate material, meaning some of the particles are water-loving and some are water-phobic. When exposed to fluids — like serum or blood — the polycarbonate self-assembles into clumps about 200 nanometers in size. Another part of the clump is positively charged, designed to match the negatively charged surface of microbes, Hedrick said.

Cell walls are dynamic barriers, constantly morphing and changing as they divide. When something binds to their surface, the walls’ synthesis is interrupted. Penicillin, for instance, binds to an enzyme that helps build the walls. Hedrick and collaborators at the Institute of Bioengineering and Nanotechnology in Singapore say the charged particles interact with the cell walls to destabilize them.

“These particles are cationic (positively charged), so they are attracted to the microbial membrane surface, and it begins to disrupt that dynamic assembly process of the membrane,” Hedrick said.

The authors also report that the particles can be used at relatively low concentrations. Hedrick said they’re not sure what makes the particles so effective, but it’s probably because they can each kill multiple cells, moving on to new targets after the membranes are so disfigured that static no longer binds the cells and nanoparticles together.

“A little of the polymer goes a long way,” Hedrick said.

After a few days of this, enzymes start breaking apart the chains that hold the particles together, said Bob Allen, senior manager at IBM-Almaden’s Advanced Materials Chemistry department.

“Think of the enzyme as a pair of scissors — it will go through and snip it. It’s just a weak link that allows you to have a degradable system,” he said.

The particles degrade to molecules of alcohol and carbon dioxide, which are removed just like anything else in the bloodstream.

IBM believes the particles could be a new way to treat drug-resistant bacteria, especially MRSA, which is frequently associated with hospital infections. The company says antibiotic-resistant bacteria is a fertile field for its polymer research labs — chemists do focus primarily on electronics, but chip-scale research translates well to research in health care, water purification, and energy, Allen said.

Hedrick and Allen cautioned that they’re not clinicians and they don’t know how the particles would be used. But they were optimistic about the possibilities.

“The applications are going to be very diverse, whether we’re talking about wound healing or dressing, skin infection, and quite possibly injections into the bloodstream,” Hedrick said. “But this is way early in the discovery process to be going there.”

A 10-minute treatment with a low-temperature plasma jet killed about 90 percent of drug-resistant bacteria infecting lab rats, according to a study to be published in the January issue of the Journal of Medical Microbiology. It involves a blowtorch spewing ionized gas around 95 degrees to 104 degrees F.

German and Russian researchers say the torch was able to kill 99 percent of the bacteria in a lab-grown biofilm and 90 percent of the bacteria in infected rats. The researchers tried it with Pseudomonas aeruginosa and Staphylococcus aureus, which are both ubiquitous in hospitals and can cause wound infections, especially in people with weakened immune systems. Both are resistant to a wide range of antibiotics.

Svetlana Ermolaeva, who led the research, said plasma therapy kills the bacteria by interfering with their DNA and surface structures — a key in fighting P. aeruginosa and S. aureus, which grow in protective biofilms. Thicker biofilms still show some resistance, but plasma treatment could be a new treatment where traditional antibiotics don’t work.

Plasma is a state of matter involving a collection of free-moving electrons and ions. Usually, high energy is needed to produce it — like a sudden electrical discharge (lightning) or nuclear fusion (a star) — but it’s tricky to make plasmas at atmospheric pressures and room temperatures. Even in cold plasmas, electrons are superheated to thousands of degrees. But by ionizing less of the molecules in a plasma, scientists can produce plasma whose heat is distributed to non-ionized molecules, making it cool — or at least lukewarm — enough to handle.

Eventually, plasma treatments could represent a better option than antibiotics, because microbes will not be able to build up resistance, Ermolaeva said.

[Medical Daily]

Light-based sterilization is nothing new – ultraviolet light can do a number on pathogens, though it also does damage to humans – but the new method uses a narrow spectrum of visible, harmless light wavelengths known as HINS (High Intensity, Narrow Spectrum) light to do the trick. HINS light excites molecules within bacteria such that they produce a chemically lethal response, in essence pushing bacteria to kill themselves. But while it drives bacteria to cell suicide, it’s harmless to humans and therefore can be incorporated into existing lighting systems in clinical environments to provide continuous sterilization of surfaces and air.

Continuous sterilization, of course, keeps infectious bacterial pathogens from spreading around places like hospital wards, where immune systems are low and the chances of infection are high.

And what of the violet hue? Some might find it a nice ambient addition to the usual bright-white aura of the average operating theater. But for the sake of consistency the team has also figured out how to integrate the HINS light with a combination of LED technologies to produce a warm white light that can be used alongside the usual hospital lighting scheme.

[University of Strathclyde via Smart Planet]

The researchers identified nine different molecules found in the insects' nervous system tissues that are toxic to bacteria but harmless to human cells. Those tissues could be used to engineer new kinds of antibiotics that are effective in treating infections that are resistant to conventional drugs.

For strains of infectious bacteria like MRSA, that could be huge. MRSA is highly-resistant to the usual battery of antibiotics used to treat bacterial infections and is particularly troublesome in hospital environments where it can take up residence and be particularly difficult to eradicate -- kind of like an infestation of cockroaches. When conventional drugs don't work, doctors have to reach deeper into their medicine bags, and some of the treatments they are forced to fall back on have very unpleasant side effects on healthy human tissue.

Considering the pharmaceutical industry is having a hard time finding novel (or profitable) ways of combating drug-resistant bacteria like MRSA, this new method could provide a cheap source of effective antimicrobial drugs. So before you go crushing that tiny little pharma factory skittering across your living room floor, think twice. Then go ahead and do it. Cockroaches are disgusting, dude.

[Eurekalert]

Some bacteria, including MRSA (methicillin-resistant Staphylococcus aureus), evolve mutations to change the shape of the active site of their enzymes, which is what antibiotics are after. The algorithm, called K* (pronounced K-star), tries to anticipate those changes.

The team modeled mutations in an MRSA enzyme called dihydrofolate reductase, which is targeted by several drugs. Almost every living thing has a version of DHFR, because it helps turn folic acid into thymidine, the "T" among the DNA nucleotides.

The K* algorithm helped the researchers find DHFR mutation candidates that would be able to block new antibiotics. This knowledge could be incorporated into a drug-design strategy -- anticipating how bacteria would mutate to fight antibiotics, and designing antibiotics around those predicted mutations.

When the team studied the mutant enzymes, they realized their structures were one reason why they were able to evade antibiotics, according to a Duke news release.

Donald's team has also studied using the K* algorithm to diagnose cancer and to design enzymes that could improve antibiotics' efficacy.

[PhysOrg]