Scientists have reported the first discovery of a promising new class of antibiotics. This discovery was unexpected because they were not aiming to discover new drugs.
This new antibiotic compound has shown promising activity against drug-resistant infections such as methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium, which are notorious for causing resistant infections in hospitalized patients.
you may like
However, the team’s original goal was not to discover new drugs. Instead, the researchers were investigating how the known antibiotic methylenenomycin A is made by a soil-dwelling bacterium called Streptomyces coelicolor.
Plants and microorganisms produce a large number of complex compounds known as secondary metabolites, many of which have useful medicinal properties for humans. Understanding how these compounds are made in living organisms and how they interact with human cells will help scientists develop effective medicines from these natural products.
The blueprint for producing these different biomolecules is held in specific collections of genes called “biosynthetic gene clusters.” By deleting individual genes from these clusters, Alkhalaf and Challis were able to eliminate a specific enzyme involved in methylenenomycin A synthesis. This research method allowed the reaction sequence to be stopped at critical points to study it in more detail, and it was possible to spot previously unobserved intermediate compounds formed during the process.
This systematic approach allowed the team to isolate two molecules never before seen, which they named premethylenenomycin C and premethylenenomycin C lactone. After thoroughly characterizing the structures of these compounds using a series of techniques, we investigated the biological activity of the molecules against a series of bacterial strains.
Premethylenenomycin C lactone has been found to be particularly promising. ”[It] is active against a variety of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Enterococcus faecium strains,” Challis and Alkharaf told Live Science.[It] 100 times better than original antibiotics at killing drug-resistant bacteria. ”
But perhaps more importantly, this new compound does not seem to induce antibiotic resistance in treated strains.
Repeated exposure to antibiotics can cause the evolution of some bacterial defense mechanisms, eventually leading to drug resistance and making future infections much more difficult to treat. In a 28-day experiment, E. faecium bacteria were exposed to increasing concentrations of premethylenenomycin C lactone, providing an excellent opportunity for resistance to develop. However, during that period, the team observed no change in the minimum inhibitory concentration, or the amount of drug required to produce a visible effect. In other words, the antibiotics retained their infection-killing activity and the bacteria had not evolved problematic resistance mechanisms.
you may like
Expanding this area of research – both to target more bacterial strains and to study the drug’s effects over longer periods of time – will be two important next steps for the team to demonstrate the full potential of the new molecule.
Stephen Cochrane, a medicinal chemist at Queen’s University Belfast in Ireland, said: “This is really great work and I think it’s a lesson. When you isolate a new molecule, you should look for new activities in that molecule.” But he cautioned that there is a big difference between compounds with antibacterial activity and antibiotics used to treat disease.
“The big challenge is to turn this into a viable drug, one that lasts long enough in the body, is non-toxic to humans, and is less likely to develop resistance,” he said.
For Alkharaf and Challis, this is exactly the direction they want to pursue next. They are currently collaborating with synthetic chemist David Lupton of Monash University in Australia to develop a chemical route to premethylenenomycin C lactone. This allows molecules to be produced from scratch through chemical synthesis, rather than relying on microorganisms to make them. This will provide larger quantities of the compound for research aimed at understanding how the molecule works and how it affects human cells.
“It would be useful to identify the biological targets of compounds in susceptible bacteria and to better understand how changes in a compound’s structure affect target binding and biological activity,” Alkhalaf and Challis said. Such insights may aid in the design of related compounds with even more potent antibiotic activity.
Source link
