Microbial 'dark matter' yield new powerful antibiotic

“Clovibactin is different. Since it 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,” Dr. Weingarth added.

Clovibactin comes from “unculturable” bacteria

The antibiotic is originally found in a species of gram-negative Betaprotobacteria, and Northwestern University biology professor Kim Lewis and researchers from Novo Biotic Pharmaceuticals, a Massachusetts-based biotech company first discovered it.

However, the researchers soon realized that 99 percent of the soil bacteria that produced Clovibactin could not be cultured in a lab, as they required a special micro-environment with specific nutrients and other symbiotic micro-organisms. 

It was impossible to create such conditions in a lab, so the researchers only decided to grow the unculturable bacteria (also called ”bacterial dark matter”), which grows only in the soil. They developed a device called iCHip that allows them to grow E terrae ssp. Carolina in soil and then isolate Clovibactin from it.

Clovibactin very efficiently targets three different cell wall precursor molecules; Lipid II, Lipid III, and C55PP. These molecules are crucial for forming a bacterial cell wall that encapsulates and protects the pathogen. 

Many previous studies suggest that chemicals like Lipid II in the cell wall allow the bacteria to evade antibiotics and play a key role in ensuring robust drug resistance. 

Clovibactin has a unique killing mechanism

Clovibactin attacks a pyrophosphate group found in all three precursor molecules and is also responsible for cell wall synthesis. It “wraps around the pyrophosphate like a tightly sitting glove. Like a cage that encloses its target,” says Weingarth. This is what gives Clovibactin its name, which is derived from the Greek word “Klouvi”, which means cage,” said Dr. Weingarth. 

Upon binding the target molecules, the antibiotic self-assembles into large fibrils on the surface of bacterial membranes. These fibrils are stable for a long time, ensuring that the target molecules remain sequestered for as long as necessary to kill bacteria. 

The researchers suggest that because the fibrils grow on bacterial membranes and not on human membranes, this is possibly the reason Clovibactin harms only bacterial cells and is non-toxic to human cells.  

“As Clovibactin only targets the immutable pyrophosphate part of precursor molecules but ignores their variable sugar-peptide moieties, it will be extraordinarily difficult for Clovibactin resistance to develop. It seems to be an end of the road in the evolution of compounds that avoid resistance,” Dr. Weingarth told Interesting Engineering.

According to the researchers, Clovibactin is quite effective against multi-drug resistant pathogens like Staphylococcus aureus and Streptococcus pneumoniae. 

The discovery and detailed knowledge of Clovibactin’s bacteria-killer mechanism is essential for the design of future antibiotics. For instance, it can give scientists a better understanding of what it takes to design antibiotics that act against the bacterial cell wall with minimal risk of resistance development. 

When asked about the current status of Clovibactin, Dallas E. Hughes, President of Novobiotic Pharmaceuticals, replied, “Clovibactin is currently in preclinical studies to determine if it has the right properties to become a clinical candidate. At that point, it will enter human trials, which typically take 2 to 3 years to complete. FDA approval will then be sought for commercialization.” 

The study is published in the journal Cell.