New compound could defeat multidrug-resistant bacteria common in hospitals

In bacterial DNA extracted from the soil, the researchers found a compound linked to the antibiotic colistin. Credit: Zach Veilleux / The Rockefeller University

For years, public health experts have sounded the alarm bells about the next phase of humanity’s coexistence with bacteria, a bleak future where emerging strains have rendered once-potent antibiotics unnecessary. The United Nations recently predicted that unless new drugs are developed, multidrug-resistant infections will push up to 24 million people into extreme poverty over the next decade and cause 10 million deaths per year. by 2050.

Scientists are especially worried about a large group of bacteria circulating in hospitals and can dodge not only blockbuster drugs like penicillin and tetracycline, but even colistin, an antibiotic long used as a crucial last option. When colistin fails, there are often no effective antibiotics for patients with multidrug-resistant infections.

Now, Rockefeller scientists are reporting their discovery of a compound that could potentially thwart resistance to colistin. In animal experiments, this potential antibiotic was very potent against dangerous opportunistic pathogens like Acinetobacter baumannii, the most common cause of infections in healthcare facilities. Posted in Nature, the results could allow the development of a new class of antibiotics to fight against strains that do not respond to any other treatment.

Evolutionary wars 

Colistin has long been used extensively in the livestock industry, and more recently in clinical settings. Overuse is believed to have put a lot of evolutionary pressure on bacteria, causing them to develop new traits in order to survive. As a result, some species have acquired a new gene called mcr-1 which escapes the toxicity of colistin, making these bacteria resistant to the drug.

Resistance to colistin spreads rapidly, in part because mcr-1 relies on a plasmid, a ring of DNA that is not part of the bulk bacterial genome and can be easily transferred from cell to cell. “It goes from one bacterial strain to another, or from one infection from one patient to another,” says Zongqiang Wang, postdoctoral associate in Sean F. Brady’s lab.

Wang and his colleagues wondered if there were any natural compounds that could be used to fight bacteria resistant to colistin. In nature, bacteria are constantly in competition for resources, developing new strategies to thwart neighboring strains. In fact, colistin itself is produced by bacteria in the soil to eliminate competitors. If a rival resists the attack by picking up mcr-1, the first microbe could subsequently acquire a new mutation, launching a new version of colistin capable of killing the mcr-1 bacteria.

“We set out to research natural compounds that soil bacteria were able to develop to fight their own colistin resistance problem,” says Brady, Professor Evnin of Rockefeller.

Like colistin, only better 

His team used an innovative approach that bypasses the limitations of traditional methods for the discovery of antibiotics. Instead of growing bacteria in the lab and looking for the compounds they produce, researchers look for genes in bacterial DNA.

Sifting through over 10,000 bacterial genomes, they found 35 clusters of genes that they believed would produce colistin-like structures. One group seemed particularly interesting because they included genes different enough from those that produce colistin to suggest they would produce a functionally distinct version of the drug.

By further analyzing these genes, the researchers were able to predict the structure of this new molecule, which they named macolacin. They then chemically synthesized this novel parent of colistin, producing a new compound without ever needing to extract it from its natural source.

Laboratory experiments have shown that macolacin is potent against several types of bacteria resistant to colistin, including inherently resistant Neisseria gonorrhoeae, a pathogen classified as a higher level threat by the Centers for Disease Control and Prevention. Colistin, on the other hand, has been shown to be completely inactive against this bacteria.

Next, the scientists tested the new agent in mice infected with XDR A. baumannii resistant to colistin, another pathogen of the highest threat. Mice injected with optimized macolacin completely cleared the infection within 24 hours, while those treated with colistin or placebo retained at least the same amount of bacteria present during the initial infection.

“Our results suggest that macolacin could potentially be developed into a drug for deployment against some of the more troubling multidrug-resistant pathogens,” Brady said.

In another study, Brady’s lab used similar methods to explore a different class of antibiotics, called menaquinone-binding antibiotics (MBA). In a book recently published in Natural microbiology, the researchers showed that, in mice, the new MBAs they identified were effective against methicillin-resistant Staphylococcus aureus, another cause of dangerous infections in healthcare facilities.

Wang adds that the evolutionary-based genome extraction method used to discover macolacin could also be applied to other drug resistance issues. “In principle, you can search bacterial DNA for new variants of any known antibiotic rendered ineffective by drug-resistant strains,” he says.

Research may help save antibiotics’ effectiveness against drug-resistant bacteria

More information:
Sean Brady, A Naturally Inspired Antibiotic To Target Multidrug-resistant Pathogens, Nature (2022). DOI: 10.1038 / s41586-021-04264-x

Lei Li et al, Identification of structurally diverse antibiotics binding to menaquinone with in vivo activity against multidrug-resistant pathogens,Natural microbiology (2021). DOI: 10.1038 / s41564-021-01013-8

Provided by Rockefeller University

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