When we humans developed antibiotics, we escalated our evolutionary war with bacteria. And now, bacteria seem to be winning. They’re developing resistance to all our antibiotics, even colistin, an antibiotic long used as a crucial last option. But perhaps we could counter the bacterial counterattack if we learn how bacteria conduct their evolutionary wars with each other. After all, bacteria have been trading blows with each other for a long time—far longer than they’ve been countering our antibiotics.

Bacterial antibiotics, or natural product antibiotics, could inspire new human-administered antibiotics. This possibility is being explored by scientists at Rockefeller University. They’ve been analyzing bacterial genome sequences to identify antibiotic congeners—alternative versions of natural product antibiotics. By resorting to congeners, antibiotic-secreting bacteria can sustain hostilities against enemy bacteria. New congeners can get around antibiotic resistance that would neutralize old congeners.

The 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”) that appeared January 5. The article proposes a solution to the resistance that bacteria have been developing to colistin. Much of this resistance is attributed to a gene called mcr-1 that helps bacteria evade colistin’s toxicity.

“Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener,” the article’s authors wrote. “Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes.”

In animal experiments, macolacin was highly potent against dangerous opportunistic pathogens like Acinetobacter baumannii, the most common cause of infections in healthcare settings. Macolacin, then, is a prospective antibiotic, and it may point to a new class of antibiotics to combat strains that respond to no other treatments.

“We set out to search for natural compounds that soil bacteria may have evolved to fight their own colistin-resistance problem,” said Brady, who is Rockefeller’s Evnin professor.

Colistin has long been abundantly used in the livestock industry, and more recently in the clinic. Colistin resistance spreads fast, in part because mcr-1 sits on a plasmid, a ring of DNA that isn’t part of the bulk bacterial genome and can transfer easily from cell to cell. “It jumps from one bacterial strain to another, or from one patient’s infection to another’s,” said Zongqiang Wang, PhD, a postdoctoral associate in Brady’s lab.

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

The Rockefeller team used an innovative approach that sidesteps the limitations of traditional methods for antibiotics discovery. Instead of growing bacteria in the lab and fishing for the compounds they produce, the researchers searched bacterial DNA for the corresponding genes.

In sifting through more than 10,000 bacterial genomes, they found 35 groups of genes that they predicted would produce colistin-like structures. One group looked particularly interesting as it included genes that were sufficiently different from those that produce colistin to suggest they would produce a functionally distinct version of the drug.

In 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 never-before-seen relative of colistin, yielding a novel compound without ever needing to extract it from its natural source.

In lab experiments, macolacin was shown to be potent against several types of colistin-resistant bacteria including intrinsically resistant Neisseria gonorrhoeae, a pathogen classified as a highest-level threat by the Centers for Disease Control and Prevention. Colistin, on the other hand, appeared to be totally inactive against this bacterium.

Next, the scientists tested the new agent in mice infected with another colistin-resistant bacterium, the extensively drug-resistant (XDR) A. baumannii. Mice that received an injection of optimized macolacin completely cleared away the infection in 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 stated, “suggest macolacin could potentially be developed into a drug to be deployed 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 (MBAs). In an article (“Identification of structurally diverse menaquinone-binding antibiotics with in vivo activity against multidrug-resistant pathogens”) published recently in Nature Microbiology, the researchers showed that, in mice, the new MBAs they identified are effective against methicillin-resistant Staphylococcus aureus, another cause of dangerous infections in healthcare settings.

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

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