New Screening Test Identifies Potential Therapies to Fight Drug-Resistant Bacteria

Assay may help repurpose approved treatments

Researchers at the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) and National Institute of Allergy and Infectious Diseases (NIAID) have found a new way to identify drugs and drug combinations that may potentially be useful in combating infections that are resistant to antibiotics. The screening method provides a potential new approach to repurposing known drugs and compounds to help deal with hospital-borne infections as well as emerging infectious diseases.

The researchers used the test to screen approximately 4,000 approved drugs and other biologically active compounds and identified 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 K. pneumoniae has been a source of fatal infections in hospitals across the United States

The researchers also used the screening test to gauge the effectiveness of combinations of drugs against antibiotic-resistant bacteria. They found three triple-drug combinations that were effective against 10 common strains of multidrug-resistant bacteria.

The study results were published in Emerging Microbes & Infections.

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 FDA-approved drugs and 14 drugs still under investigation. They included antibiotics, antifungals, antiseptics, and a triple 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 use in different ways that we have never used before,” said NCATS scientist Wei Zheng, PhD. “We’re hoping this approach will lead to approvable, effective ways to combat dangerous infections by drug-resistant bacteria.”

In recent years, a growing 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, Zheng said.

The researchers realized that simply identifying the 25 active drugs and compounds would not be enough to potentially help patients with drug-resistant infections. Some of the compounds were only weakly active.

The researchers decided to look for drug combinations that might work against antibiotic-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 K. pneumoniae organisms sensitive again to a standard-of-care antibiotic. And that is what the scientists found.

They identified four sets of two-drug combinations that suppressed the growth of multidrug-resistant K. pneumoniae. Antibiotics that previously were inactive because of resistance became active against K. pneumoniae in the presence of the second drug. For example, while the antibiotic colistin is ineffective against drug-resistant K. pneumoniae, the investigators found that combining colistin with 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 that three sets of three-drug combinations had the most activity, and think these three combinations eventually may be useful to clinicians.”

The scientists hope the new screening technology can be developed to help clinicians make “real-time” treatment decisions for highly resistant infections.

Zheng thinks that the screening test could become an important addition to the clinician’s toolbox, although commercialization is still some time away. “It can provide crucial information for a rapid response to emerging infectious diseases,” he said.

Source: NIH; November 9, 2016.