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Penetrating Protein Battles Drug-Resistant Bacteria

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A bacteria-puncturing peptide could be a new tool against antibiotic resistance. | Carla Schaffer / A. de Breij et al. / AAAS

A new antibacterial agent could be a promising addition to humanity's arsenal in the ongoing battle against antibiotic-resistant bacteria. In findings published January 10 in Science Translational Medicine, the new compound even eradicated stubborn pathogens growing together in tough-to-treat microbial mats called biofilms, which are complex communities that can be 10 to 1,000 times more tolerant to antibiotics than free-living bacteria.

Antibiotic resistant bacteria sicken at least 2 million people every year in the United States, causing as many as 23,000 fatalities. The death toll is predicted to rise as more and more microbial "bugs" evolve and become immune to existing drugs.

Seeking alternatives to conventional antibiotics, Anna de Breij and colleagues at Leiden University Medical Center in the Netherlands developed SAAP-148 — a short protein fragment, or peptide, that kills bacteria by poking holes in their outer membranes.

SAAP-148 was effective against multiple multidrug resistant bacteria belonging to the ESKAPE panel, a pernicious group of pathogens including Staphylococcus aureus and Klebsiealla pneumoniae that have been highlighted by the Infectious Diseases Society of America for their potential to escape antibiotics and cause human harm. Notably, none of the treated microbes developed the ability to escape killing by the peptide.

"The best surprise was the finding that the synthetic peptide did not induce resistance in bacteria," said Peter Nibbering, an associate professor at Leiden University Medical Center and senior author on the paper.

Antibiotics typically take the form of small molecules that each interfere with one very specific process inside a bacterial cell. Although the drugs can be quite potent, their specificity can be a shortcoming because rapidly mutating microbes can develop new genetic variants of these antibiotic targets that allow the microbe to resist the drug.

"We were looking for agents that display a mode of action very different from those of current antibiotics," said Nibbering.

The scientists drew inspiration from built-in components of the human body's innate defenses called antimicrobial peptides, which act in concert with other components of the immune system to help prevent infections.

"Natural antimicrobial peptides are designed by nature to optimally exert multiple functions in the human body," said Nibbering. "By focusing on a single function, such as antibacterial activity, it may be possible to further optimize a peptide's structure," he said.

After synthesizing and screening hundreds of artificial peptides for antibacterial activity, the researchers narrowed in on SAAP-148. The new peptide adopts a three dimensional shape that penetrates bacterial envelopes more efficiently compared to its natural counterparts.

SAAP-148 eliminated bacteria growing in biofilms in culture — even killing the highly resistant populations of so-called "persister cells," which exist in a dormant, drug-tolerant state that can drive the reemergence of infections after antibiotic treatment. What's more, an ointment containing the peptide effectively treated wounds infected with methicillin-resistant Staphylococcus aureus (MRSA) and the increasingly common hospital infection bacterium Acinetobacter baumannii in mice and on laboratory samples of human skin.

A clinical trial to evaluate whether the ointment can treat antibiotic resistant infections in human patients is scheduled for 2018.

[Credit for associated biofilm image: Scott Chimileski and Roberto Kolter, Harvard Medical School, Boston/ NIH Image Gallery]