Researchers decode new antibiotic agent
More and more bacterial pathogens are developing resistance. There is an increasing risk that current drugs will no longer be effective against infectious diseases. Scientists around the world are therefore searching for new active agents. Researchers at the University of Bonn, the German Center for Infection Research (DZIF), Utrecht University (Netherlands), Northeastern University in Boston (USA) and the company NovoBiotic Pharmaceuticals in Cambridge (USA) have now jointly discovered a new highly effective antibiotic in a soil bacterium and elucidated its mode of action. Clovibactin attacks the cell wall of bacteria, including numerous multidrug-resistant “superbugs.” The results have now been published in the renowned journal Cell.
“We urgently need new antibiotics to stay ahead in the race against bacteria that have become resistant,” says Prof. Tanja Schneider of the Institute for Pharmaceutical Microbiology at the University of Bonn and the University Hospital Bonn. She adds that in recent decades, not many new substances to combat bacterial pathogens have come onto the market. “Clovibactin is novel compared to current antibiotics,” says the co-spokesperson of the Transregional Collaborative Research Center “Antibiotic CellMAP,” who is also a member of the Transdisciplinary Research Area “Life & Health” and the Cluster of Excellence “ImmunoSensation2” as well as deputy coordinator of the DZIF research area New Antibiotics. Together with the German Center for Infection Research (DZIF), the Institute of Pharmaceutical Microbiology specialises in deciphering the mode of action of antibiotic candidates.
The soil bacterium Eleftheria terrae subspecies carolina bears its place of origin in its name: It was isolated from a soil sample in the US state of North Carolina and produces the active substance clovibactin to protect itself from competing bacteria. “The new antibiotic simultaneously attacks the structure of the bacterial cell wall at several sites by blocking essential building blocks,” explains Tanja Schneider. With unusual intensity, it attaches itself specifically to these building blocks and kills the bacteria by destroying their cell envelope.
Clovibactin encloses the target structure like a cage
The interdisciplinary researchers have jointly deciphered exactly how this works. The team led by Prof. Kim Lewis of the Antimicrobial Discovery Center at Northeastern University in Boston (USA) and the company NovoBiotic Pharmaceuticals in Cambridge (USA) discovered clovibactin using the iCHip device. This allows bacteria to be grown in the laboratory that were previously considered unculturable and therefore unavailable for the development of new antibiotics.
“Our discovery of this exciting new antibiotic further validates the iCHip culturing technology in the search for new therapeutic compounds from previously uncultivated microorganisms,” says Dr Dallas Hudges, president of NovoBiotic Pharmaceutical, LLC. The company has demonstrated that clovibactin has very good activity against a broad spectrum of bacterial pathogens and has successfully treated mice with it in model studies.
The mode of action of the new antibiotic was elucidated by researchers led by DZIF scientist Tanja Schneider. The Bonn researchers were able to show that clovibactin binds selectively and with high specificity to pyrophosphate groups of bacterial cell wall components. Prof. Markus Weingarth’s group from the Department of Chemistry at Utrecht University in the Netherlands has uncovered exactly what this bond looks like. Using solid-state NMR spectroscopy, the researchers deciphered the structure of the complex of clovibactin and the bacterial target structure lipid II. These studies, which took place under conditions similar to those found in the bacterial cell, showed that clovibactin encompasses the pyrophosphate group. Hence the name "Clovibactin", derived from the Greek “Klouvi” (cage), because it encloses the target structure like a cage.
Combined attack minimises development of resistance
Clovibactin acts primarily on Gram-positive bacteria. These include methicillin-resistant Staphylococcus aureus (MRSA), known as "hospital germs," as well as the pathogens that cause widespread tuberculosis, which affects many millions of people worldwide. “We are very confident that the bacteria will not develop resistance to clovibactin so quickly,” says Tanja Schneider. That’s because the pathogens cannot change the cell wall building blocks so easily to undermine the antibiotic—so their Achilles’ heel remains.
But clovibactin can do even more. After docking at the target structures, clovibactin forms supramolecular filamentous structures that tightly enclose the target structures and further damage the bacterial cells. Bacteria that encounter clovibactin are also stimulated to release certain enzymes, known as autolysins, which then uncontrollably dissolve their own cell envelope. “The combination of these different mechanisms is the reason for the exceptional resilience to resistance,” says Tanja Schneider. This shows what potential still lies in the natural diversity of bacteria that are candidates for new antibiotics.
“Without the interdisciplinary cooperation between the partners, this important step in the fight against resistance would not have succeeded,” says Prof. Markus Weingarth. The research team now plans to use its findings to further increase the effectiveness of clovibactin. “But there is still a long way to go before a new antibiotic hits the market,” says Tanja Schneider.
Participating institutions and funding:
In addition to the Institute for Pharmaceutical Microbiology and the Clausius Institute for Physical and Theoretical Chemistry at the University of Bonn, participants in this study included the German Center for Infection Research (DZIF), Utrecht University (Netherlands), NovoBiotic Pharmaceutical in Cambridge (USA), the Rijksuniversiteit Groningen (Netherlands), the University of Tübingen, Tianjin Medical University (China), the Novartis Institutes for Biomedical Research in Cambridge (USA), the University of Florence (Italy), the Consorzio Interuniversitario Risonanze Magnetiche di Metallo Proteine in Sesto Fiorentino (Italy) and Northeastern University in Boston (USA). The DZIF and the Transregional Collaborative Research Center “Antibiotic CellMAP” of the German Research Foundation funded the project in Bonn and Tübingen.
