Compound nestled in parasitic worm offers promise as antibiotic against obstinate superbugs
A compound domiciled inside the gut of a soil-dwelling parasitic worm could be the chief ingredient for a potent human antibiotic designed to fight a class of stubborn superbugs, new research suggests.
The tsunami of antibiotic resistance is an acute global threat. In the United States, at least 2.8 million people get an antibiotic-resistant infection each year, and more than 35,000 people die, according to a recent report by the CDC.
The beleaguered field of antibiotics is desperate for a winner. For one of the biggest threats to global health, the lion’s share of antibiotic development is taking place in a handful of labs of small biopharma companies or the halls of academia, while big pharma largely focuses on more lucrative endeavors. Meanwhile, most freshly approved antibiotics have been more potent versions of existing classes of antibiotics. In short, the field is desperate for fresh options.
The compound, darobactin, is a product of Photorhabdus bacteria that was discovered residing within the gut of a nematode.
Darobactin has the potential to smother Gram-negative bacteria, which cause infections such as typhoid, cholera and the plague. The class of microbes brandishes a resilient outer membrane which assists them in subverting most standard antibiotics. The last class of antibiotics acting against Gram-negative bacteria was developed in the 1960s, researchers noted in Nature.
Research on mice, conducted by a team of scientists led by Kim Lewis, professor of biology and director of the Antimicrobial Discovery Center at Northeastern University, indicated that darobactin treated E. coli and Klebsiella pneumoniae infections, sans any toxicity.
The discovery marks the first instance that the animal microbiome was found to harbor an antibiotic that could be employed in humans, Lewis noted in a report published by Northeastern accompanying the Nature publication.
Nematodes and Photorhabdus bacteria share their dinners, primarily of the insect variety. The nematode sets its friend the Photorhabdus bacteria loose on say, a caterpillar. The bacteria expels toxins into the unassuming caterpillar, killing it — allowing the conniving allies to share the spoils.
But, the Photorhabdus must also fend off other greedy diners — particularly from within nematode’s gut, which is typically brimming with the same Gram-negative bacteria that attack humans. And because the nematode is the Photorhabdus’s home, it makes sure what kills the gram-negative pathogens doesn’t strangle its host.
“Since Photorhabdus bacteria live in the nematode, and the nematode is an animal just like we are, whatever they make has to be non-toxic [for us],” Lewis said in the Northeastern report.
That additional armor that Gram-negative bacteria enjoy is engineered by a protein called BamA, which acts as a guard, opening its gates cyclically allowing the passage of fresh proteins to build that impervious protective shield. Darobactin makes a beeline for BamA and clogs that gate, thwarting the creation of that cell wall and rendering the gram-negative bacteria vulnerable to existing antibiotics.
The researchers are now gunning to test the BamA inhibitor in human trials.
This mechanism of action potentially resolves the intractable problem of penetrating the barrier of Gram-negative bacteria, they wrote in Nature. “There are only two essential proteins exposed on the surface of the outer membrane – BamA; and LptD17. There is little doubt that nature produced more than one type of compounds acting against these targets.”
The Nature article included the contributions of scientists from Northeastern University, Purdue University, and the J. Craig Venter Institute from the United States; Justus Liebig University Giessen, the German Center for Infection Research DZIF and the European Molecular Biology Laboratory EMBL in Germany; as well as the University of Basel in Switzerland.
Image credit: Andy Murray, A Chaos of Delight