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With antibiotic-resistant 鈥渟uperbugs鈥� now infecting 2 million people per year and a dearth of new medications in the pipeline to treat them, CU 麻豆影院 researchers are taking a novel approach to addressing the looming public health crisis:
They鈥檙e helping develop new drugs to make old drugs work better.
鈥淲e believe the compounds we鈥檝e discovered have the potential to rejuvenate existing antibiotics 鈥� to make bacteria that are now insensitive to multiple drugs sensitive again,鈥� said Corrie Detweiler, a professor of Molecular, Cellular and Developmental Biology (MCDB) who recently outlined her discovery in the journal .
More than 23,000 people die annually in the United States from bacterial infections that have evolved to resist antibiotics. Thousands more suffer life-threating bouts with once-easily treatable illnesses like strep throat, urinary tract infections and pneumonia. And some forms of tuberculosis and gonorrhea are now resistant to all available drugs.
鈥淎s our antibiotics work less and less, we risk essentially going back to a period 200 years ago when even a minor infection could mean death,鈥� said Detweiler. 鈥淓ven the risk from routine procedures like knee surgery is going to go up.鈥�
Meanwhile, most antibiotics still in use today were developed in the 1950s, as pharmaceutical companies have scaled back investment in research and development. The last time a new class of antibiotics hit the market was in 1984, according to the Pew Charitable Trust.
鈥淲ith industry largely turning away, it鈥檚 up to academic labs like ours to step up and help feed the pipeline,鈥� said Detweiler.
Corrie Detweiler in her lab at CU 麻豆影院.听(Credit: Patrick Campbell/CU 麻豆影院)
A new way to fight superbugs
To that end, she recently developed a new technique called SAFIRE for screening for new small molecules with anti-microbial properties.
鈥淭he old way of discovering antibiotics helped us get to the low-hanging fruit, but that stopped working a long time ago,鈥� she said.
Rather than pour potential new antibiotics into a test tube teeming with bacteria (as in the past) SAFIRE uses cutting-edge cell imaging techniques to observe what the compounds do to mammalian cells infected with bacteria over 18 hours.
The method enables her laboratory to zero in on compounds that keep bacteria from replicating inside the host cell, but don鈥檛 harm the host.
鈥淭his filters out toxic compounds right off the bat,鈥� she said.
Of 14,400 potential candidates screened, her team has zeroed in on at least three with strong potential.
They work not by killing the bacteria itself, but by getting inside it and shutting of cellular machines called 鈥渆fflux pumps鈥� which bacteria use to protect themselves from both antibiotic medications and the body鈥檚 own immune-boosting proteins.
听鈥淏acteria are really smart, and they have learned to use these pumps to pump out whatever we throw at them to kill them, so they can live happily,鈥� said Edward Yu, a professor of pharmacology at Case Western Reserve University who collaborated with Detweiler on the research. 听鈥淭he compounds Corrie is working on inhibit those pumps.鈥�
Collaborating with industry
Senior research assistant Amy Crooks, right, works with Corrie Detweiler in the lab.
Yu notes that because the compounds don鈥檛 kill the bacteria themselves, the bacteria don鈥檛 learn to resist them 鈥� a fact that could give the treatments more staying power than conventional antibiotics have had.
The compounds are also potent.
In the recently published study, they synergized with the common antibiotics erythromycin and ciproflaxin to reduce replication of Salmonella in infected cells by 10 to 20 fold .
In September, the Colorado Office of Economic Development and International Trade awarded Detweiler $125,000, topping off $2 million in National Institutes of Health funding.
She鈥檚 now collaborating with 麻豆影院-based pharmaceutical start-up Crestone Inc. to help refine the compounds, and hopes to begin testing them in animals soon.
听鈥淚f you had a patient who had an infection that was resistant to available antibiotics, you might someday be able to treat them by giving them one of our compounds in addition to the antibiotic,鈥� she said. 鈥淚t could not only make the old antibiotic work better but also make the patient鈥檚 own immune system work better. It鈥檚 exciting to think about.鈥�
Other co-authors of the PLOS Pathogens paper include: Abigail Reens, MCDB graduate student and first-author; Amy Crooks, senior research assistant; Toni Nagy, postdoctoral research associate; graduate student David Reens, Jessica Podoli, Madeline Edwards; Edward Yu and Chih-Chia Su of Case Western University.
