In preclinical studies, the antimicrobial, clovibactin, was shown to have susceptibility against a broad spectrum of pathogens and also worked against a specific bacteria in 2 animal studies.
An investigational antibiotic, clovibactin, was shown to have activity against several pathogens as well successfully treated mice infected with Staphylococcus aureus.
The study’s results were published in Cell.
Clovibactin appears to have a novel approach as It targets not just 1, but 3 different precursor molecules that are all essential for the construction of the cell wall, an envelope-like structure that surrounds bacteria according to the investigators. This was discovered by Tanja Schneider, PhD, and a group of investigators from the University of Bonn in Germany—she is one of the paper’s coauthors.
“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.”
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,” said Markus Weingarth, PhD, a researcher from the Chemistry Department of Utrecht University, and the paper's senior author. “Clovibactin hence has potential for the design of improved therapeutics that kill bacterial pathogens without resistance development.”
Multidrug resistance continues to be a major public health threat when it comes to bacterial and fungal infections. Pathogenic resistance to antibiotics can appear in a short amount of time and create treatment challenges.
Finding an Antibiotic in Sandy Soil
Typically, antibiotics are developed in the lab by tweaking existing antimicrobials and modify treatments by adding new molecules to make them susceptible against pathogens.
One of the novel aspects of the antibiotic is the way in which it was discovered.
“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," said Weingarth.
Clovibactin was discovered by NovoBiotic Pharmaceuticals, a small US-based early-stage company, and microbiologist Kim Lewis, PhD, Northeastern University who is also a company cofounder. They developed a device called iCHip that can grow ‘bacterial dark matter,’ which are unculturable bacteria. In fact, 99% of all bacteria are ‘unculturable’ and could not be grown in laboratories previously, hence they could not be mined for novel antibiotics. Using iCHip, the researchers discovered Clovibactin in a bacterium isolated from a sandy soil from North Carolina: E. terrae ssp. Carolina.
Although it is in the earliest stages in the lab, its mechanism of action, offers a glimpse of its potential long-term viability. “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.”
Long term, the investigators say this offers a glimpse of how antimicrobials may be developed going forward. “Clovibactin’s action against the PPi of cell wall precursors, a simple immutable target, expands our understanding of antibiotics evolved to avoid resistance, and points the way to rationally designing compounds with a long clinically useful life.”