Antibiotic-resistant bacteria may succumb to natural products

When we humans developed antibiotics, we intensified our evolutionary war on bacteria. And now the bacteria seem to be winning. They develop resistance to all of our antibiotics, even colistin, an antibiotic long used as a crucial last option. But maybe we could counter the bacterial counterattack if we learned how bacteria wage their evolutionary wars with each other. After all, bacteria have been trading blows with each other for a long time, much longer than they have thwarted our antibiotics.

Bacterial antibiotics, or antibiotics from natural products, could inspire new antibiotics administered by humans. This possibility is being explored by scientists at Rockefeller University. They analyzed the sequences of the bacterial genome to identify congeners of antibiotics, alternative versions of natural antibiotics. By using congeners, antibiotic-secreting bacteria can fuel hostilities against enemy bacteria. The new congeners can bypass the resistance to antibiotics which would neutralize the old congeners.

Rockefeller scientists, led by Sean F. Brady, PhD, presented their latest findings in Nature, in an article (“A naturally inspired antibiotic to target multidrug-resistant pathogens“) Released Jan. 5. The article offers a solution to the resistance bacteria develop to colistin. Much of this resistance is attributed to a gene called mcr-1 which helps bacteria escape the toxicity of colistin. colistin.

“Bioinformatics analysis of sequenced bacterial genomes has identified a group of biosynthetic genes that should encode a structurally divergent colistin congener,” wrote the authors of the article. “Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and inherently resistant pathogens with phosphoethanolamine transferase genes encoded in the chromosomes.”

In animal experiments, macolacin was very potent against dangerous opportunistic pathogens like Acinetobacter baumannii, the most common cause of infections in healthcare facilities. Macolacin is therefore a potential antibiotic, and it could indicate a new class of antibiotics to fight against strains that do not respond to any other treatment.

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

Colistin has long been used extensively in the livestock industry, and more recently in clinical settings. 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 passes from one bacterial strain to another, or from one infection from one patient to another,” said Zongqiang Wang, PhD, postdoctoral associate at 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.

The Rockefeller team used an innovative approach that bypasses the limitations of traditional methods for antibiotic discovery. Instead of growing bacteria in the lab and looking for the compounds they produce, the researchers looked 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, the molecule they named macolacin. The researchers then chemically synthesized this novel parent of colistin, producing a new compound without ever needing to extract it from its natural source.

In laboratory experiments, macolacin has been shown to be 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, scientists tested the new agent in mice infected with another colistin-resistant bacteria, extensively drug-resistant (XDR). A. baumannii. 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 findings,” Brady said, “suggest that macolacin could potentially be developed into a drug for deployment against some of the most troubling multidrug-resistant pathogens.”

In another study, Brady’s lab used similar methods to explore a different class of antibiotics, called menaquinone-binding antibiotics (MBA). In an article (“Identification of structurally diverse menaquinone-binding antibiotics with in vivo activity against multidrug-resistant pathogens”) Recently published in Natural microbiology, the researchers have shown that, in mice, the new MBAs they have identified are effective against methicillin resistance Staphylococcus aureus, another cause of dangerous infections in healthcare facilities.

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