The world needs new antibiotics: In view of the increasing resistance problem, the search for new agents against bacterial pathogens is under high pressure. Researchers have now succeeded in doing so: They have found substances from the group of so-called glycopeptides that have a very different effect than common antibiotics. Because instead of blocking the build-up of the bacterial cell wall, they prevent its breakdown – an important process for cell division. Initial experiments suggest that, thanks to this strategy, the agents are also effective against multi-resistant germs such as MRSA.
They were once the most powerful weapon in medicine against bacterial pathogens. But many antibiotics have lost their impact in the meantime. Due to the uncontrolled and mass use of these drugs, more and more disease-causing bacteria are developing resistance. Many pathogens, including the MRSA hospital germ or the ESBL bacteria, are even immune to several classes of active substances. In view of this worrying development, the World Health Organization (WHO) is also raising the alarm: A few years ago, it publicly called for alternatives to the previously common means to be sought.
Elizabeth Culp of McMaster University in Hamilton and her team may have found an alternative like this. They report the discovery of antimicrobial substances that have a very different effect than common antibiotics. For their study, the scientists devoted themselves to the so-called glycopeptide antibiotics. These substances are naturally produced by soil bacteria. They act primarily against gram-positive pathogens and are already used as so-called reserve antibiotics. However, many compounds from the group of glycopeptides have not yet been researched in detail.
Different genes, different effects?
That’s exactly what Culp and her colleagues wanted to do. Specifically, their search focused on the family tree and the genes of the bacterial producers of such glycopeptides. Because certain genetic building instructions can be associated with known resistance mechanisms. According to the researchers’ idea, glycopeptides without these traits could be potential candidates for new antibiotics – and attack bacteria via mechanisms other than those known. “Our hypothesis was that the genes that make these antibiotics different could also have them kill bacteria differently,” explains Culp.
In fact, this suspicion was confirmed. The scientists found two compounds that have unique mechanisms of action. One of these substances is a newly discovered glycopeptide that Culps Team calls Corbomycin. The other connection is the well-known but little-researched complestatin. Both antibiotics attack bacteria with a special strategy. They prevent the remodeling of the bacterial cell wall, as examinations using imaging techniques revealed.
Bacteria in prison
“The cell wall not only gives the bacteria their shape, but also gives them strength and is important for their survival,” says Culp. “Antibiotics like penicillin kill bacteria by preventing the synthesis of this wall – but the antibiotics we found do the opposite.” Corbomycin and Complestatin prevent the so-called remodeling of the peptidoglycans, which are the building blocks of the bacterial cell wall. In this way, they block the degradation of this protective shell. However, this conversion process is essential for the multiplication of the bacteria. “For cells to grow, they have to divide and spread. If the breakdown of the cell wall is completely prevented, the bacteria are trapped like in a prison. They cannot spread, ”explains the researcher.
According to the scientists, the two substances are the first known antibiotics that kill pathogens in this way. But how well does this work in practice? In the first tests with mice, Culp and her colleagues applied the antibiotics in the form of creams to the skin. You should fight methicillin-resistant Staphylococcus aureus (MRSA) infections. The result: Both agents were able to significantly reduce the bacterial load. After 33 hours, the concentration of the pathogens had decreased about a hundredfold, as the team reports. This also improved the rodents’ overall health.
The search continues
The researchers’ conclusion is that their novel mode of action and the fact that they appear to have the power to fight multi-resistant bacteria make corbomycin and complestatin promising drug candidates. In the future, they want to continue looking for potential new antibiotics: “Our approach can be transferred to other antibiotics and help to find other compounds that show new modes of action,” concludes Culp. In fact, further discoveries are already emerging: some members of the family of active substances from corbomycin and complestatin could fight bacteria using a comparable mechanism.
Source: Elizabeth Culp (McMaster University, Hamilton) et al., Nature, doi: 10.1038 / s41586-020-1990-9