Enormous Need for New Antibiotics
The need for new antibiotics is immense. A publication in the highly respected journal “Cell” has drawn attention to this issue. Here, a group led by Dr. Rhythm Shukla from the University of Utrecht in the Netherlands and Aaron J. Peoples from NovoBiotic Pharmaceuticals in Cambridge, USA, reports on a new antibiotic with very interesting properties: Clovibactin.
Isolating Clovibactin from Uncultivable Bacteria
Researchers isolated Clovibactin from the soil bacterium Eleftheria terrae subspecies carolina, which was previously considered uncultivable. It was only with the help of a device developed by NovoBiotic called iCHip, which isolates and cultivates bacteria in their natural soil environment, that they succeeded in enriching E. terrae subspecies carolina and its metabolites sufficiently. Clovibactin not only inhibits the growth of drug-resistant gram-positive bacterial pathogens through a new mechanism of action, but it is also said to be resistant to resistances.
Clovibactin Forms a Cage Around the Bacterium
The structure of Clovibactin bears some resemblance to the cyclic depsipeptide Teixobactin. The ring-shaped depsipeptide structure in both antibiotics is formed from four amino acids. In the linear N-terminus, which is three amino acids shorter than Teixobactin, two D-amino acids are included.
Observation that Bacillus subtilis cells treated with Clovibactin exhibited deformations known as blebbing, typically caused by many cell-wall-active antibiotics, led researchers to investigate its mechanism of action. Solid-state NMR spectroscopy, in particular, revealed that the antibiotic binds to three different target structures. These are three different precursor molecules, all essential for building the bacterial cell wall, or the murein sacculus.
Clovibactin binds extremely tightly to the pyrophosphate residues in the peptidoglycan precursors undecaprenyl pyrophosphate (C55PP), Lipid I, and Lipid II. The fact that the pyrophosphate residues are the target structure for the antibiotic is remarkable because this small structural feature is present in all gram-positive bacteria, while the other details of the murein components around the pyrophosphate group can vary.
Detailed investigations showed that Clovibactin, in a sense, encloses the pyrophosphate group like a cage. Hence, the name “Clovibactin,” derived from the Greek word “Klouvi” for cage.
In a press release, Professor Dr. Tanja Schneider from the Institute of Pharmaceutical Microbiology at the University of Bonn, who was also involved in the study with her team, said, “The combination of these different mechanisms is the reason for its exceptional resistance to resistances.” Professor Dr. Markus Weingarth from the University of Utrecht, one of the senior authors, told “Genetic Engineering & Biotechnology News,” “Clovibactin is different because it was isolated from bacteria that couldn’t be cultivated before. Therefore, pathogenic bacteria have never seen such an antibiotic and had no time to develop resistance.”
Effective Against a Wide Range of Gram-Positive Bacteria
Clovibactin showed antibacterial activity against a broad spectrum of gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), daptomycin-resistant and vancomycin-intermediate-resistant S. aureus strains (VISA), as well as hard-to-treat vancomycin-resistant Enterococcus faecalis and E. faecium (vancomycin-resistant enterococci, VRE). Compared to an E. coli WO153 strain with a defective outer membrane, Escherichia coli was only slightly affected at 100 µg/ml (the highest tested concentration), probably due to inadequate penetration of the drug.
A single dose of Clovibactin was administered intravenously to mice at a dosage of up to 40 mg/kg and was well tolerated. Furthermore, mice treated with Clovibactin were protected from a lethal Staphylococcus aureus infection.
How effective and well-tolerated Clovibactin truly is and whether the optimistic assessment of its resistance to resistance development is sustainable will require further studies.
Original source: This information was Initially covered by PZ.de and has been translated for our readers.
