New antimicrobial glycopeptides
Antibiotics with a new mechanism of action
The world needs new antibiotics: due to the problem of growing resistance, the search for new agents against bacterial pathogens is under high pressure. Researchers have now succeeded in this: they have found substances from a group of so-called glycopeptides that have a completely different effect than conventional antibiotics. Because instead of blocking the build–up of the bacterial cell wall, they prevent its destruction - an important process for cell division. Initial experiments show that thanks to this strategy, the agents are also effective against multi-resistant microbes such as MRSA.
Antibiotics were once the most powerful weapon against bacterial pathogens. But many antibiotics have lost their effect over time. Due to the uncontrolled and mass use of these drugs, an increasing number of pathogenic bacteria develop resistance. Many pathogenic microorganisms, including the hospital microbe MRSA or ESBL bacteria, are even immune to several classes of active substances. In connection with this alarming event, the World Health Organization (WHO) also raises the alarm: several years ago, it publicly called for alternatives to previously common remedies.
Elizabeth Culp of McMaster University in Hamilton and her team may have found such an alternative. They report the detection of antimicrobial substances that have a completely different effect than conventional antibiotics (Antibiotics discovered that kill bacteria in a new way – VM). For their research, scientists devoted themselves to the so-called glycopeptide antibiotics. These substances are naturally produced by soil bacteria. They act mainly 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 studied in detail.
Different genes, different effects?
That's exactly what Culp and her colleagues wanted to do. In particular, their search is focused on the family tree and the genes of bacterial producers of such glycopeptides. Because certain genetic instructions may be associated with known resistance mechanisms. According to the researchers, glycopeptides without these signs may be potential candidates for new antibiotics – and attack bacteria using mechanisms other than those known. "Our hypothesis was that the genes that distinguish these antibiotics can also kill bacteria in different ways," explains Culp.
In fact, this suspicion was confirmed. Scientists have discovered two compounds with unique mechanisms of action. One of these substances is a newly discovered glycopeptide, which the researchers called corbomycin. Another compound is the well–known but little-studied complexatin. Both antibiotics affect bacteria according to a special strategy. They prevent bacterial cell wall remodeling, as studies using imaging techniques have shown.
Bacteria in prison
"The cell wall not only gives bacteria their shape, but also gives them strength and is essential for their survival," says Culp. "Antibiotics such as penicillin kill bacteria by preventing the synthesis of this wall, but the antibiotics we found work the other way around." Corbomycin and complestatin prevent the so-called remodeling of peptidoglycans, which are the building blocks of the bacterial cell wall. Thus, they block the destruction of this protective shell. However, this transformation process is of great importance for the reproduction of bacteria. "In order for cells to grow, they must divide and spread. If the destruction of the cell wall is completely prevented, the bacteria fall into a trap, like in a prison. They cannot spread," the researcher explains.
According to scientists, these two substances are the first known antibiotics that kill pathogens in this way. But how well does it work in practice? In the first tests on mice, Culp and her colleagues applied antibiotics to the skin in the form of creams. You must fight methicillin-resistant Staphylococcus aureus (MRSA) infections. Result: both agents were able to significantly reduce the bacterial load. According to the team, after 33 hours, the concentration of pathogenic microorganisms decreased by about a hundred times. It also improved the overall health of the rodents.
The search continues
The researchers concluded that their new mode of action and the fact that they appear to be effective against multi-resistant bacteria make corbomycin and complexatin promising drugs. In the future, they want to continue the search for potential new antibiotics: "Our approach can be transferred to other antibiotics and will help to find additional compounds that demonstrate new ways of action," concludes Culp. In fact, new discoveries are already emerging: some members of the family of active substances from corbomycin and complostatin can fight bacteria using a comparable mechanism.
Article by Culp et al. Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling is published in the journal Nature.
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