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Resistant Superbugs Killed by New Antibiotic From Bacterial “Dark Matter”

A hand grasping a molecule, showing how clovibactin can tightly wrap around special lipids in bacterial cell membranes.
Credit: Markus Weingarth
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A study has isolated a powerful new antibiotic – clovibactin – from soil bacteria previously considered “unculturable”, demonstrating that it kills bacteria in a way that is less likely to lead to antibiotic resistance. The research is published in Cell.

Delving into bacterial “dark matter”

Antibiotic resistance is a growing problem, described by the World Health Organization as “one of the biggest threats to global health, food security and development today”. When bacteria acquire resistance to the very drugs meant to eliminate them, this can lead to increased medical costs, prolonged hospital stays and even increased mortality.

While there are approaches that can help slow the development of resistance, novel and effective antibiotics are needed. Very few antibiotics are entering clinical development, with most “new” drugs resembling older, existing ones.

Most antibiotics used today – such as streptomycin, vancomycin and tetracycline – originate from natural compounds produced by soil-dwelling bacteria. However, approximately 99% of bacterial species – the so-called bacterial “dark matter” – have not been able to be cultured in the lab, preventing them from being studied as a source of new antibiotics.

In the current study, researchers from Utrecht University isolated an antibiotic compound, clovibactin, from a previously “unculturable” soil bacteria. Clovibactin successfully eliminated infections in mice using an “unusual” mechanism that the researchers say is less likely to lead to resistance.

A multi-target mechanism

The researchers studied a species of soil bacteria previously thought to be “unculturable” – Eleftheria terrae ssp Carolina, named after the sandy soil in North Carolina from which it was isolated – as a potential source of new antibiotic compounds.

“Unculturable bacteria cannot be grown in standard laboratory conditions,” said Dr. Markus Weingarth, associate professor at Utrecht University and senior author of the study, speaking to Technology Networks. “NovoBiotic Pharmaceuticals, together with Prof. Kim Lewis and other researchers from Northeastern University, has developed a device called iCHip that allows bacteria to grow in their natural environment, e.g., to grow a soil bacterium like the one that produces clovibactin in its natural soil.”

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With E. terrae ssp Carolina successfully cultured, the researchers found that the isolated clovibactin successfully killed Gram-positive bacteria – a subset of bacteria with a single, thick cell wall – that were resistant to other antibiotics. Experiments revealed that it works by blocking the growth of the cell wall, a technique used by many other antibiotics – but clovibactin goes about it in an unusual way.

It binds three different precursor molecules that are essential parts of cell wall construction, bypassing the variable sugar-peptide parts and wrapping tightly around its targets. This unique method of action earned clovibactin its name, which is derived from the Greek word “klouvi”, meaning “cage”.

“As clovibactin only binds to the immutable, conserved part of its targets, bacteria will have a much harder time developing any resistance against it. In fact, we did not observe any resistance to Clovibactin in our studies,” Weingarth explained in a press release.

“This is important as the more killing mechanisms an antibiotic uses, the less likely the emergence of antimicrobial resistance,” he added.

Experiments in mice with compromised immune systems infected with Staphylococcus aureus bacteria showed that Clovibactin was similar to the established antibiotic vancomycin in reducing the infection.

“This potent antibiotic holds the promise of enabling the design of improved therapeutics that kill bacterial pathogens without resistance development,” the authors write in the study.

Weingarth highlights that the discovery of clovibactin – as well as similar compounds such as teixobactin and lassomycin – validates that previously “unculturable” bacteria are a promising source for novel antibiotics.

Reference: Shukla R, Peoples AJ, Ludwig KC, et al. An antibiotic from an uncultured bacterium binds to an immutable target. Cell. 2023. doi: 10.1016/j.cell.2023.07.038

Dr. Markus Weingarth was speaking to Dr. Sarah Whelan, Science Writer for Technology Networks.