Drug-resistant bacteria are thwarting the world’s last-resort antibiotics, leading scientists to seek new compounds from poisonous frogs, backyard soil bacteria, and other wildlife. Now, scientists have found the makings of an exceptional microbe killer inside us: By tweaking a naturally occurring peptide—a short chain of amino acids—found in the human body, researchers have designed a drug that could wipe out obstinate microbes resistant to all available treatments.
The candidate, now headed to human trials for skin infections, adds “an important piece … to the puzzle of creating a perfect antibiotic,” says Kim Lewis, a microbiologist at Northeastern University in Boston who was not involved in the work.
When a small subset of bacteria survives antibiotic treatment, an infection can get out of control fast. As these resilient microbes thrive, they can group together on a surface—like a wound or a medical device—and encase themselves in a slimy protective layer known as a biofilm. Such colonies are hard for drugs to penetrate, and they harbor dormant cells called persisters that can quietly weather an antibiotic assault only to come roaring back later. Such infections “are the really nasty things for patients,” says immunologist Peter Nibbering at Leiden University Medical Center in the Netherlands.
Nibbering and a team of Dutch collaborators are trying to combat these biofilm-associated infections by improving on a human peptide called LL-37, which helps regulate the body’s immune response. LL-37 already has some natural bacteria-killing abilities, and the researchers previously shortened the peptide to make a more powerful variant, consisting of 24 of the 37 original amino acids. In the new work, they optimized this peptide by making a series of random replacements to its building blocks without disrupting its overall structure.
One variation, dubbed SAAP-148, proved a powerful little weapon, the team reports online today in Science Translational Medicine. Whereas most traditional antibiotics target specific groups of bacteria and kill by disrupting key mechanisms of those microbes, SAAP-148 is more of a generalist. It kills by damaging most any bacterium’s plasma membrane, causing it to spill its contents and deflate.
SAAP-148 eradicated Staphylococcus aureus and Acinetobacter baumannii—two leading causes of hospital-acquired infections that often defy available treatments—on both biofilm-covered human skin samples in a dish and infected wounds on the backs of mice.
It also managed to knock out persister cells in a bacterial biofilm that had already been treated with the antibiotic rifampicin, often used to fight persistent infections at the site of prostheses. This is the first published demonstration of the killing of such persisters, notes Bob Hancock, a microbiologist at the University of British Columbia in Vancouver, Canada, whose team is also developing antimicrobial peptides.
The drug also appears to overcome what Hancock calls “one of the big bedevilments” of antibiotic candidates: The environment of the human body inhibits the activity of many such molecules because they stick to proteins and lipids in the blood. SAAP-148 looks to be one of the few known peptides that kills bacteria efficiently without also binding to these circulating obstacles in serum, he notes.
Nibbering and colleagues also report that S. aureus didn’t manage to develop resistance to SAAP-148 after repeated exposures. That’s surprising, says Tim Tolker-Nielsen, a microbiologist at the University of Copenhagen’s biofilm research center, though he notes that resistance could still develop under different conditions.
For now, Nibbering’s team—and a university spinoff company called Madam Therapeutics—are pursuing SAAP-148 to treat topical infections, such as skin wounds, bladder infections, or infections at the site of prostheses. To administer the drug systemically, they’re working to design an injectable formulation that protects the peptide from breaking down in the body, makes it more selective, and directs it to the site of infection. Nibbering plans to test SAAP-148 in clinical trials soon—first to disinfect lesions from the inflammatory skin disease atopic dermatitis, then to treat the infected wounds of burn patients—once an ethical review board gives its approval.