New powerful antibiotic Clovibactin seems capable of combating harmful bacteria, and even multi-resistant ‘superbugs’, in a way that makes it more difficult for bacteria to develop resistance against it.
Researchers from Utrecht University (Netherlands), Bonn University (Germany), the German Center for Infection Research (DZIF), Northeastern University of Boston (USA), and NovoBiotic Pharmaceuticals (USA) shared the discovery of Clovibactin in the scientific journal Cell.
Antibiotic resistance is a huge health threat. In July, a report by University of Queensland (UQ) researchers warned a global crisis of antibiotic resistance is inevitable, and the UK government recently announced up to £210 ($267) million of funding to tackle antimicrobial resistance (AMR).
“We urgently need new antibiotics to combat bacteria that become increasingly resistant to most clinically used antibiotics,” said Dr Markus Weingarth, a researcher from the Chemistry Department of Utrecht University. “Since Clovibactin was isolated from bacteria that could not be grown before, pathogenic bacteria have not seen such an antibiotic before and had no time to develop resistance.”
Unculturable bacteria
Clovibactin was discovered by NovoBiotic Pharmaceuticals and microbiologist Professor Kim Lewis from Northeastern University, Boston. Earlier, they developed a device that enables researchers to grow ‘bacterial dark matter’, which are so-called unculturable bacteria.
Ninety-nine percent of all bacteria are ‘unculturable’ and could not be grown in laboratories previously, and therefore not be mined for novel antibiotics. Using the device, called iCHip, the researchers discovered Clovibactin in a bacterium isolated from a sandy soil from North Carolina: E. terrae ssp. Carolina.
In the joint Cell publication, NovoBiotic Pharmaceuticals shows that Clovibactin successfully attacks a broad spectrum of bacterial pathogens. It was also successfully used to treat mice infected with the superbug Staphylococcus aureus.
Unusual killing mechanism
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 Professor Tanja Schneider from the University of Bonn in Germany, one of the paper’s co-authors.
Schneider said: “The multi-target attack mechanism of Clovibactin blocks bacterial cell wall synthesis simultaneously at different positions. This improves the drug’s activity and substantially increases its robustness to resistance development.”
Weingarth’s team from Utrecht University used a technique called solid-state nuclear magnetic resonance (NMR) that allowed the study of Clovibactin’s mechanism under similar conditions as in bacteria.
“Clovibactin wraps around the pyrophosphate like tight glove, like a cage that encloses its target,” says Weingarth. This is what gives Clovibactin its name, which is derived from Greek word ‘Klouvi’, meaning cage.
Non-toxic to human cells
The remarkable aspect of Clovibactin’s mechanism is that it only binds to the immutable pyrophosphate that is common to cell wall precursors, but it ignores that variable sugar-peptide part of the targets.
Upon binding the target molecules, it 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,” says Weingarth. “Clovibactin hence has potential for the design of improved therapeutics that kill bacterial pathogens without resistance development.”
Read the full paper in Cell: A new antibiotic from an uncultured bacterium binds to an immutable target.
Edited by Diana Spencer, Senior Digital Content Editor, Drug Discovery World
