A look one thousand years into the past is revealing clues about how to develop the bacteria-fighting drugs of the future.
A concoction from a 10th century medical manuscript damaged cell membranes, altered the expression of disease-promoting genes and interfered with interbacterial communication when added to bacterial cultures, researchers report September 3 in mSphere. What’s more, three kinds of harmful bacteria developed resistance to the medicinal mixture much more slowly compared with conventional single-molecule antibiotics.
“The difference is remarkable,” says Omar El-Halfawy, a microbiologist at the University of Regina in Canada who was not involved in the research.
This impaired ability to develop resistance may occur because the medieval medicine affects several bacterial targets, says Freya Harrison, a microbiologist at the University of Warwick in England. For bacterial colonies to survive, “they’ve potentially got to mutate multiple targets, and that’s difficult.”
Currently, antibiotic-resistant infections kill more than 1 million people each year. But humans have been battling the minuscule enemies that cause diseases like plague, leprosy and tuberculosis for millennia. Sometime in the 10th century, Anglo-Saxon scribes compiled several sometimes-dubious treatments into a medical text known as Bald’s Leechbook.
In 2015, Harrison and a team of microbiologists and historians brewed a remedy from the Leechbook, called Bald’s eyesalve, in the lab. They mixed garlic, onion, bovine bile and wine in a brass vessel, then allowed it to stand for nine days. In laboratory tests, Bald’s eyesalve displayed surprisingly effective antimicrobial activity against both Staphylococcus aureus and its drug-resistant form, MRSA.
This time, the scientists set out to determine how the eyesalve affected pathogens, measuring how the brew altered gene expression in bacterial cultures. After eyesalve treatment, hundreds of S. aureus genes were expressed differently, including ones related to cell membrane composition and disease-causing potential.
The remedy also damaged bacterial membranes, a possibly lethal maneuver. Furthermore, very low concentrations of the eyesalve reduced S. aureus’ ability to create hardy antibiotic-resisting colony formations called biofilms. It also inhibited bacterial cell communication, which pathogens use to coordinate activities and become more harmful.
Finally, the team dosed cultures of S. aureus and two other pathogens with increasing concentrations of the eyesalve or commonly used antibiotics to see how quickly resistance developed. After two weeks, the microbes often flourished despite exposure to eight to sixteen times the amount of the traditional antibiotic that had stymied their growth at the beginning. In contrast, they could only tolerate slightly higher eyesalve concentrations.
Harrison says she’s not expecting people to whip up their own batches of eyesalve to treat infections. “It would be really impractical to do that, and also potentially really unreliable and dangerous because it’s going to be so variable.”
Instead, she says, researchers could recapitulate the eyesalve’s multipronged attack in a clinically suitable way with a lab-made cocktail containing a handful of the potion’s active ingredients. “Somewhere in there, there’s this combination of molecules that’s responsible for most of this effect — so, can we find out what they are?”
