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An artist's sketch of the Salmonella bacteria. Illustration by Tom Voss
An artist's sketch of the Salmonella bacteria. Illustration by Tom Voss
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In the world of bacteria, there are the good, the bad and the ugly.

Ugly bacteria are those that take human lives quickly and ruthlessly—like the virulent strain of E. coli that killed 52 people in northern Germany within five weeks last summer. These highly dangerous microbes adapt and survive by developing resistance to the broad spectrum antibiotics commonly prescribed by doctors.

Now scientists are fighting back, using novel technologies to combat the deadliest pathogens while protecting the good bacteria necessary for human life.

“This work is going to move science forward
in a very important way.”

Stanley Maloy, Ph.D., dean of SDSU’s College of Sciences, is part of a nationwide team selected by the National Institutes of Health (NIH) to build targeted antibiotic treatments rapidly and in response to specific epidemics. The team’s EUREKA grant supports highly innovative scientific exploration to advance public health.
 
Risk-averse pharmas won’t touch this kind of unconventional research because the payback is uncertain. Scientists, on the other hand, look beyond the financial rewards of discovery. There’s a good reason why the EUREKA grant is named for Archimedes’ reputed shout of triumph at an early scientific breakthrough.

“This work is going to move science forward in a very important way,” Maloy said. “We are not putting another brick in an existing wall; we are building the wall. Even if our research doesn’t provide a perfect solution, NIH believes others will use this approach to proceed to the next level.”

A catalog of microbes

Maloy’s work coincides with an overarching NIH initiative known as the Human Microbiome Project, which is sequencing the genomes of bacterial microbes living on the human body.

In 2003, geneticists rocked the scientific world by completing a 13-year project to identify and map the genetic makeup of the human species. Known as the Human Genome Project, this international initiative sequenced the chemical base pairs that make up human DNA.

While cell genetics is often credited for longevity or blamed for obesity and cancer, scientists now understand that the true genetic makeup of an individual comprises the cell genome plus the bacterial genome. Not surprising, since microbial genes outnumber human genes by 1,000 to 1.

The Human Microbiome Project will catalog the microbial communities found at various sites on the human body—skin, oral cavities, gastrointestinal tract—analyze their role in human health and disease and ultimately, try to manipulate more of them to work on humanity’s behalf.

Building on success

The EUREKA grant awarded to Maloy and company builds on the Human Genome Project’s success in identifying DNA sequences from the microbiome of hundreds of healthy individuals. By comparing these with the microbiomes of people infected with killer bacteria, Maloy and his colleagues hope to target the “ugly” bacteria and develop specific antibiotics to treat each strain.

Here’s how it works:

Using advanced information technology, Eric Jakobsson, Ph.D., at the University of Illinois at Urbana-Champaign identifies the dangerous sequence in Salmonella or E. coli and designs a similar sequence that will bind to the original.

Maloy then evaluates the new sequence to determine if the alteration is radical enough to inhibit production of the undesirable protein while leaving other proteins to carry out their beneficial functions.

In the third step, Jeff Brinker, Ph.D., at the University of New Mexico Los Alamos, employs nanotechnology to load the inhibitors into “wheelbarrows,” virus-like particles that will bind to the bacteria.

Finally, back at SDSU, Maloy tests the effectiveness of the particles before they are delivered selectively and efficiently to kill the pathogenic bacteria and leave the good bacteria intact.

“We are engineering these viruses,” Maloy explained. “They don’t exist in nature. And then we’re loading them in a way that natural viruses could not be loaded.

“Once you get it working, there are millions of other applications for human health. Our research may help manipulate the human microbiome so that one day the most serious bacterial infections can be eliminated from the population.”

Push the envelope

This combination of nanotechnology, comparative genomics and microbiology to target specific bacteria has never been attempted before. If the team is successful in targeting Salmonella —one of the model genetic organisms—their work could forever change the treatment of bacterial illness.

Maloy’s career prepared him well to push the envelope in microbiome research. Before coming to SDSU, he studied Salmonella at the University of Illinois at Urbana-Champaign and collaborated with a scientist in Chile on Salmonella Typhi, which causes typhoid fever. Up to 30 percent of those who contract the disease die if not treated with antibiotics, Maloy said.

“In trying to understand why Salmonella Typhi infects humans only and how it is different from the good bacteria in our guts, we did a lot of genetic comparisons between bacteria,” Maloy said. “And that is how I moved from doing basic research to research related to pathogens.”

In 2005-2006, Maloy was elected president of the American Society for Microbiology, the oldest and largest life science membership organization in the world with more than 39,000 members. He continues to collaborate with his colleague in Chile on the possible link-between long term bacterial infection and liver cancer.

Next up: personalized medicine

The contributions of Maloy and other scientists to a better understanding of the human microbiome could lead to breakthroughs in preventative medicine and health maintenance. Researchers in the field expect to discover relationships in the next few years between the pattern of bacteria in a person’s gut and the general state of his or her health.

From there, it’s a small step to personalized medicine. Imagine physicians designing individualized health regimes based on each patient’s genomic and microbiomic makeup. Yes, the doctor will cure you now.

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