YSM Issue 90.1
Create successful ePaper yourself
Turn your PDF publications into a flip-book with our unique Google optimized e-Paper software.
iomedical engineering<br />
FEATURE<br />
the food supply. Nursing homes and hospitals are other major breeding<br />
grounds for antibiotic-resistant bacteria. “In nursing homes, infections<br />
are commonly suspected and antibiotics are frequently prescribed.<br />
Older nursing home residents have multiple medical problems and are<br />
often exposed to multiple rounds of antibiotics” said Juthani, whose<br />
expertise involves infections in older adults. Although scientists and<br />
government agencies have encouraged farmers and medical professionals<br />
to limit antibiotic use, no strict regulations have been passed.<br />
For some infections, we are running out of treatment options. “We<br />
are more often stuck using very toxic, old antibiotics because we have<br />
no choice,” said Juthani. In some cases, even these last resorts are failing.<br />
Each time a bacterial infection becomes resistant to a particular<br />
drug, physicians can only hope that a new, more effective drug will<br />
be developed. Unfortunately, because bacteria generally develop resistance<br />
to a drug very quickly and thereby render it obsolete, antibiotic<br />
development is not profitable for pharmaceutical companies. “There<br />
have only been one or two new antibiotics developed in the last 30<br />
years,” said Greg Qiao from the University of Melbourne in a Science<br />
Daily article.<br />
That’s where the real stars come in. A team of Australian scientists—<br />
including Qiao, Eric Reynolds, and PhD candidate Shu Lam—recently<br />
published a paper in Nature Microbiology describing a promising alternative<br />
technology to combat multidrug-resistant bacteria. Instead<br />
of designing a traditional chemical drug treatment, the team developed<br />
what they call “structurally nanoengineered antimicrobial peptide<br />
polymers,” or SNAPPs, for short. The researchers were inspired<br />
by natural antimicrobial peptides, which are small proteins that play<br />
important roles in the immune systems of many organisms. Naturally<br />
occurring antimicrobial peptides cannot be used in clinical settings<br />
because they are often toxic to mammalian cells, but Lam and her<br />
team wanted to use them as a model for designing a powerful and safe<br />
antibiotic agent.<br />
The scientists meticulously designed the polymers down to the level<br />
of the individual building blocks—amino acids—that would make up<br />
the peptides. Out of the many amino acids available to them, the scientists<br />
chose lysine and valine. Lysine is a positively charged cation and<br />
was selected because cationic peptides were already known to exhibit<br />
antimicrobial activity. Valine, on the other hand, is uncharged and<br />
therefore hydrophobic, meaning it does not interact favorably with<br />
water or other polar molecules. Since hydrophobic materials interact<br />
favorably with other hydrophobic materials, valine’s hydrophobicity<br />
enables the SNAPPs to infiltrate the cell membrane, which is also<br />
mostly hydrophobic. Instead of just creating long chains of amino acids<br />
or allowing the polymers to self-assemble, the researchers attached<br />
groups of 16 or 32 chains to a multifunctional core, which served to<br />
promote water solubility and create the characteristic star shape. They<br />
hypothesize that the star shape optimizes functionality because it promotes<br />
peptide aggregation and localized charge concentration, which<br />
leads to more effective ionic interactions with bacterial membranes.<br />
After designing and successfully producing the polymers, the researchers<br />
assessed the activity of the SNAPPs against different species<br />
of bacteria. The SNAPPs were active against all bacterial species but<br />
were especially effective against Gram-negative bacteria, such as E.<br />
coli. Gram-negative bacteria are characterized by an outer membrane<br />
that normally acts as a highly impermeable barrier, but the researchers<br />
discovered that the SNAPPs could penetrate this membrane, since<br />
they have a high affinity for specific molecules found on it. The treatment<br />
was equally effective against antibiotic-resistant and susceptible<br />
strains of bacteria. The effectiveness of SNAPPs against Gram-negative<br />
bacteria is especially important because no antibiotic drugs currently<br />
under development are effective against Gram-negative infections.<br />
Before testing SNAPPs in living organisms, the researchers first performed<br />
a biocompatibility assay to ensure that the polymers would<br />
not attack mammalian cells. By incubating the polymers with sheep’s<br />
blood and measuring death rates of blood cells, the scientists determined<br />
that SNAPPs exhibit very low toxicity, even at concentrations<br />
100 times higher than what is required to kill bacteria. After confirming<br />
biocompatibility, they tested the effectiveness of SNAPPs by<br />
treating mice with rampant bacterial infections. The results were very<br />
promising—all mice treated with SNAPPs lived, compared to only<br />
20 percent of the untreated mice. In addition, SNAPP treatment enhanced<br />
the ability of white blood cells to infiltrate infected tissues, a<br />
benefit not displayed by mice treated with traditional antibiotics.<br />
The SNAPPs have multiple mechanisms of killing cells, making it<br />
more difficult for bacteria to develop resistance against them. The<br />
polymers’ partially hydrophobic composition allows them to infiltrate<br />
the membrane, but once they have done so, the positively charged<br />
amino acids disrupt membrane integrity and prevent regulation of ion<br />
flow. The star-shaped polymers can even aggregate and rip apart the<br />
membrane. The SNAPPs may also trigger the cellular processes that<br />
induce apoptosis, or cell suicide. All these mechanisms of antibiotic<br />
action are impressive individually, but when combined in a single molecule,<br />
they are incredibly powerful and difficult for bacteria to fight.<br />
Even after exposing 600 generations of bacteria to low concentrations<br />
of SNAPPs, the researchers could not detect bacterial resistance to the<br />
treatment. These results show great promise for SNAPPs as a longterm<br />
solution to the rise of superbugs.<br />
To bring treatments like SNAPPs into regular use, more research,<br />
development, and eventually clinical trials are needed. Although many<br />
industries and the public still fail to heed scientists’ warnings about antimicrobial<br />
resistance, governments and research institutions are starting<br />
to focus on the war against drug-resistant bacteria. On September<br />
21st, the United Nations held a summit on antimicrobial resistance<br />
and concluded that all countries must formulate a plan to combat it.<br />
At the beginning of October, the CDC announced that a Yale School of<br />
Public Health research team—along with 33 other teams—will receive<br />
funding as part of a $14 million effort to research antibiotic resistance.<br />
Hopefully, this collaboration between scientists and governments will<br />
allow SNAPPs—and perhaps other new technologies—to better aid in<br />
humanity’s battle against antibiotic-resistant bacteria.<br />
IMAGE COURTESY OF WIKIMEDIA COMMONS<br />
►Scanning electron micrograph image of methicillin-resistant<br />
Staphylococcus aureus (MRSA). MRSA is one of the most well-known<br />
drug-resistant bacteria and is especially common in hospitals and<br />
sports settings.<br />
www.yalescientific.org<br />
December 2016<br />
Yale Scientific Magazine<br />
31