Thursday 6 January 2022

New colistin variant outmanoeuvres pathogens


The United Nations recently projected that, unless new drugs are developed, multidrug-resistant infections will force up to 24 million people into extreme poverty within the next decade and cause 10 million annual deaths by 2050.


Scientists are especially apprehensive about a broad group of bacteria that circulate 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 is often no effective antibiotics for patients with multidrug-resistant infections.


Rockefeller scientists report on the discovery of a compound that could potentially outmanoeuvre colistin resistance. In animal experiments, this prospective antibiotic was highly potent against dangerous opportunistic pathogens like Acinetobacter baumannii, the most common cause of infections in healthcare settings.


Colistin has long been abundantly used in the livestock industry, and more recently in the clinic. The overuse is believed to have put a staunch evolutionary pressure on bacteria, compelling them to develop new traits to survive. As a result, some species have acquired a new gene called mcr-1 that evades colistin's toxicity, making these bacteria resistant to the drug.


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.


The researchers 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 neighbouring 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 scientists 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 search 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, which they named macolacin. They 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 colistin-resistant XDR A. baumannii, another highest-level threat pathogens. 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.




Zongqiang Wang, Bimal Koirala, Yozen Hernandez, Matthew Zimmerman, Steven Park, David S. Perlin, Sean F. Brady. A naturally inspired antibiotic to target multidrug-resistant pathogens. Nature, 2022; DOI: 10.1038/s41586-021-04264-x


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

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