New antibiotic sourced from 'microbial dark matter'

A powerful new antibiotic, dubbed ‘clovibactin’ and isolated from bacteria that could not be studied before, seems capable of combating harmful bacteria and even multi-resistant ‘superbugs’ in an unusual manner, making it more difficult for the bacteria to develop any resistance against it.

Antimicrobial resistance is a major problem for human health, and researchers worldwide are looking for new solutions. However, the discovery of new antibiotics is a challenge: few new antibiotics have been introduced over the last decades, and they often resemble older, already known antibiotics.

Clovibactin was discovered by NovoBiotic Pharmaceuticals, a small US-based early-stage company, and microbiologist Professor Kim Lewis from Northeastern University in Boston. They had previously developed a device that enables researchers to grow microbial dark matter, which are so-called unculturable bacteria. (Interestingly, 99% of all bacteria are ‘unculturable’ and could not be grown in laboratories previously, and therefore not be mined for novel antibiotics.)

Using their device, called iCHip, the US researchers discovered clovibactin in a bacterium isolated from a sandy soil from North Carolina: E. terrae ssp. Carolina. Since clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and have had no time to develop resistance.

In a study published in the journal Cell, NovoBiotic Pharmaceuticals showed that clovibactin successfully attacks a broad spectrum of bacterial pathogens. It was also successfully used to treat mice infected with the superbug Staphylococcus aureus.

Clovibactin appears to have an unusual killing mechanism. It targets not just one, but three different precursor molecules that are all essential for the construction of the cell wall, an envelope-like structure that surrounds bacteria. This was discovered by the group of study co-author Professor Tanja Schneider, from the University of Bonn.

“The multi-target attack mechanism of clovibactin blocks bacterial cell wall synthesis simultaneously at different positions,” Schneider said. “This improves the drug’s activity and substantially increases its robustness to resistance development.”

How exactly clovibactin blocks the synthesis of the bacterial cell wall was unravelled by a team led by Dr Markus Weingarth at Utrecht University. They utilised solid-state nuclear magnetic resonance (NMR) spectroscopy, which allows clovibactin’s mechanism to be studied under similar conditions as in bacteria.

“Clovibactin wraps around the pyrophosphate like a tight glove, like a cage that encloses its target,” Weingarth said. Furthermore, clovibactin only binds to the pyrophosphate that is common to cell wall precursors, ignoring that variable sugar-peptide part of the targets.

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

Furthermore, upon binding the target molecules, clovibactin self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time and thereby ensure that the target molecules remain sequestered for as long as necessary to kill bacteria.

“Since these fibrils only form on bacterial membranes and not on human membranes, they are presumably also the reason why clovibactin selectively damages bacterial cells but is not toxic to human cells,” Weingarth said. “Clovibactin hence has potential for the design of improved therapeutics that kill bacterial pathogens without resistance development.”

Image caption: The jars contain various cell wall precursors that the Bonn researchers isolated for analysis, including the target structures of clovibactin. Photo ©Gregor Hübl/University of Bonn.