Researchers at the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS), Clinical Center and National Institute of Allergy and Infectious Diseases (NIAID) have created a new way to identify drugs and drug combinations that may potentially be useful in combating infections that are resistant to many different antibiotics. They developed an assay (test) to rapidly screen thousands of drugs to determine how effective they were against a variety of types of resistant bacteria.
The screening method provides a potential new approach to repurpose
known drugs and compounds to potentially help deal with powerful,
hospital-borne infections, as well as emerging infectious diseases.
NCATS scientist Wei Zheng, Ph.D.,
and NIH colleagues Peter Williamson, M.D., Ph.D., of NIAID, and Karen
Frank, M.D., Ph.D. of the Clinical Center, used the test to screen
approximately 4,000 approved drugs and other biologically active
compounds, identifying 25 that suppressed the growth of two
drug-resistant strains of Klebsiella pneumoniae that have become
resistant to most major types of antibiotics. Drug-resistant Klebsiella
has been a source of fatal infections in many hospitals across the
The researchers also used the screening test to gauge the
effectiveness of combinations of drugs against antibiotic-resistant
bacteria in this study. They found three different three-drug
combinations that were effective against 10 common strains of
The results were published Nov. 9, 2016, in the journal Emerging Microbes & Infections (link is external).
NIH: The new screening test applies high-throughput screening technology
to examine thousands of drugs and compounds that inhibit bacterial
growth. The 25 newly identified drugs and compounds consisted of 11 U.S.
Food and Drug Administration-approved drugs, and 14 drugs still under
investigation. They include antibiotics, antifungals, antiseptics, and
an antiviral, antimalarial and anticancer drug/compound. “The results are very promising, and we think that the test can
eventually help repurpose approved drugs and other compounds and find
clinically relevant drug combinations that can be approved for to use in
different ways that we have never used before,” Zheng said. “We’re
hoping this approach will lead to approvable, effective ways to combat
dangerous infections by drug-resistant bacteria.”
In recent years, an alarming number of increasingly drug-resistant
and sometimes life-threatening bacterial strains have begun to emerge,
especially in the hospital setting. For the most part, hospitals don’t
have the capability to quickly test large numbers of drugs — and
combinations of drugs — against drug-resistant bacterial infections,
The researchers realized that simply identifying the 25 active drugs
and compounds would not be enough to potentially help patients with a
drug-resistant infection. Some of the compounds were only weakly active,
and at low and ineffective concentrations.
The researchers decided to look for combinations of drugs that might
work against the drug-resistant bacteria. They paired newly identified
drugs from the repurposing screen with a standard-of-care antibiotic
that did not work by itself. The goal was to make the drug-resistant
Klebsiella pneumoniae sensitive again to a standard-of-care antibiotic.
That’s just what the scientists found. They identified four sets of
two-drug combinations that suppressed the growth of multidrug-resistant
Klebsiella pneumoniae. Those antibiotics that previously were inactive
due to resistance now became active against Klebsiella pneumoniae in the
presence of the second drug.
For example, while the antibiotic colistin is completely ineffective
against drug-resistant Klebsiella pneumoniae, they showed that combining
colistin with the drug doxycycline reversed the drug resistance.
The researchers also examined three-drug combinations of broad-acting
antibiotics that may be given immediately in the clinic to patients
with severe infections, when doctors have little time to make decisions.
They screened for 10 commonly seen drug-resistant bacterial strains.
“We wanted to see which three-drug combinations made sense,” Zheng
said. “We screened hundreds of drugs against Klebsiella pneumoniae, and
tested 15 combinations against the 10 strains. We found three sets of
three-drug combinations had the most activity, and think these three
combinations eventually may be useful to clinicians.” The scientists
hope this technology can be developed to help clinicians make
“real-time” treatment decisions for several highly resistant infections.
Zheng thinks that the screening test could become an important
addition to the clinician’s toolbox, though commercialization is still
some time away. “It can provide crucial information for a rapid response
to emerging infectious diseases,” he said.