YSM Issue 90.1

iomedical engineering
FEATURE
the food supply. Nursing homes and hospitals are other major breeding
grounds for antibiotic-resistant bacteria. “In nursing homes, infections
are commonly suspected and antibiotics are frequently prescribed.
Older nursing home residents have multiple medical problems and are
often exposed to multiple rounds of antibiotics” said Juthani, whose
expertise involves infections in older adults. Although scientists and
government agencies have encouraged farmers and medical professionals
to limit antibiotic use, no strict regulations have been passed.
For some infections, we are running out of treatment options. “We
are more often stuck using very toxic, old antibiotics because we have
no choice,” said Juthani. In some cases, even these last resorts are failing.
Each time a bacterial infection becomes resistant to a particular
drug, physicians can only hope that a new, more effective drug will
be developed. Unfortunately, because bacteria generally develop resistance
to a drug very quickly and thereby render it obsolete, antibiotic
development is not profitable for pharmaceutical companies. “There
have only been one or two new antibiotics developed in the last 30
years,” said Greg Qiao from the University of Melbourne in a Science
Daily article.
That’s where the real stars come in. A team of Australian scientists—
including Qiao, Eric Reynolds, and PhD candidate Shu Lam—recently
published a paper in Nature Microbiology describing a promising alternative
technology to combat multidrug-resistant bacteria. Instead
of designing a traditional chemical drug treatment, the team developed
what they call “structurally nanoengineered antimicrobial peptide
polymers,” or SNAPPs, for short. The researchers were inspired
by natural antimicrobial peptides, which are small proteins that play
important roles in the immune systems of many organisms. Naturally
occurring antimicrobial peptides cannot be used in clinical settings
because they are often toxic to mammalian cells, but Lam and her
team wanted to use them as a model for designing a powerful and safe
antibiotic agent.
The scientists meticulously designed the polymers down to the level
of the individual building blocks—amino acids—that would make up
the peptides. Out of the many amino acids available to them, the scientists
chose lysine and valine. Lysine is a positively charged cation and
was selected because cationic peptides were already known to exhibit
antimicrobial activity. Valine, on the other hand, is uncharged and
therefore hydrophobic, meaning it does not interact favorably with
water or other polar molecules. Since hydrophobic materials interact
favorably with other hydrophobic materials, valine’s hydrophobicity
enables the SNAPPs to infiltrate the cell membrane, which is also
mostly hydrophobic. Instead of just creating long chains of amino acids
or allowing the polymers to self-assemble, the researchers attached
groups of 16 or 32 chains to a multifunctional core, which served to
promote water solubility and create the characteristic star shape. They
hypothesize that the star shape optimizes functionality because it promotes
peptide aggregation and localized charge concentration, which
leads to more effective ionic interactions with bacterial membranes.
After designing and successfully producing the polymers, the researchers
assessed the activity of the SNAPPs against different species
of bacteria. The SNAPPs were active against all bacterial species but
were especially effective against Gram-negative bacteria, such as E.
coli. Gram-negative bacteria are characterized by an outer membrane
that normally acts as a highly impermeable barrier, but the researchers
discovered that the SNAPPs could penetrate this membrane, since
they have a high affinity for specific molecules found on it. The treatment
was equally effective against antibiotic-resistant and susceptible
strains of bacteria. The effectiveness of SNAPPs against Gram-negative
bacteria is especially important because no antibiotic drugs currently
under development are effective against Gram-negative infections.
Before testing SNAPPs in living organisms, the researchers first performed
a biocompatibility assay to ensure that the polymers would
not attack mammalian cells. By incubating the polymers with sheep’s
blood and measuring death rates of blood cells, the scientists determined
that SNAPPs exhibit very low toxicity, even at concentrations
100 times higher than what is required to kill bacteria. After confirming
biocompatibility, they tested the effectiveness of SNAPPs by
treating mice with rampant bacterial infections. The results were very
promising—all mice treated with SNAPPs lived, compared to only
20 percent of the untreated mice. In addition, SNAPP treatment enhanced
the ability of white blood cells to infiltrate infected tissues, a
benefit not displayed by mice treated with traditional antibiotics.
The SNAPPs have multiple mechanisms of killing cells, making it
more difficult for bacteria to develop resistance against them. The
polymers’ partially hydrophobic composition allows them to infiltrate
the membrane, but once they have done so, the positively charged
amino acids disrupt membrane integrity and prevent regulation of ion
flow. The star-shaped polymers can even aggregate and rip apart the
membrane. The SNAPPs may also trigger the cellular processes that
induce apoptosis, or cell suicide. All these mechanisms of antibiotic
action are impressive individually, but when combined in a single molecule,
they are incredibly powerful and difficult for bacteria to fight.
Even after exposing 600 generations of bacteria to low concentrations
of SNAPPs, the researchers could not detect bacterial resistance to the
treatment. These results show great promise for SNAPPs as a longterm
solution to the rise of superbugs.
To bring treatments like SNAPPs into regular use, more research,
development, and eventually clinical trials are needed. Although many
industries and the public still fail to heed scientists’ warnings about antimicrobial
resistance, governments and research institutions are starting
to focus on the war against drug-resistant bacteria. On September
21st, the United Nations held a summit on antimicrobial resistance
and concluded that all countries must formulate a plan to combat it.
At the beginning of October, the CDC announced that a Yale School of
Public Health research team—along with 33 other teams—will receive
funding as part of a $14 million effort to research antibiotic resistance.
Hopefully, this collaboration between scientists and governments will
allow SNAPPs—and perhaps other new technologies—to better aid in
humanity’s battle against antibiotic-resistant bacteria.
IMAGE COURTESY OF WIKIMEDIA COMMONS
►Scanning electron micrograph image of methicillin-resistant
Staphylococcus aureus (MRSA). MRSA is one of the most well-known
drug-resistant bacteria and is especially common in hospitals and
sports settings.
www.yalescientific.org
December 2016
Yale Scientific Magazine
31