A recipe for effective antibiotics?
Researchers provide "blueprint" for promising drug candidatesRead out
Bacteria kill: antibiotics can only succeed if they penetrate into the cell interior of the germs. Researchers have now discovered which properties give chemical compounds this important ability. In the experiment, her "blueprint" has already proven itself. Through targeted modifications, they modified an active ingredient against Gram-positive bacteria so that it also mastered the difficult-to-penetrate cell wall of Gram-negative pathogens. In the future, the results in the search for new antibiotics could help, writes the team in the journal "Nature".
Antibiotics have long been considered the best weapon of medicine against bacterial pathogens. Meanwhile, many of these funds are increasingly ineffective. Because worldwide, more and more germs are developing resistance - even here in Europe. Many bacteria, including the hospital germ MRSA or the ESBL bacteria, are even immune to several drug classes. In view of this development, the World Health Organization has recently urged to explore new alternatives.
But the search for potential antibiotics is difficult. Especially against Gram-negative bacteria such as Escherichia coli or Pseudomonas aureginosa there are hardly any promising candidates. The problem: unlike gram-positive microorganisms, their outer cell membrane is such that it is virtually impossible to penetrate for active substances. "Means that manage to do so are usually gained through a specific door in the membrane: a so-called porin, " says Paul Hergenrother of the University of Illinois in Urbana. However, only a handful of drug classes are known which succeed in gaining access in this way.
Molecules in the test
The scientist and his colleagues, led by Study Director Michelle Richter, have now systematically investigated the properties of a chemical compound needed to cross the hurdle and get it inside the pathogens. In short, which formula could lead to successful antibiotics against Gram-negative bacteria? To find out, the team initially tested a variety of complex molecules exemplarily on the E. coli germ. The active ingredients were originally derived from plants or microbes from nature, but had been modified in the laboratory.
In fact, only a few test candidates successfully penetrated into the cell interior of the bacteria. However, all those who made it had a certain aspect in their blueprint in common: "They had amines - molecular components that contain the element nitrogen, " reports Hergenrother. However, conversely, not all active ingredients with amines made their way into the germs. What distinguished the successful from the unsuccessful candidates? displayThe modified drug 6DNM-Amin Brian Stauffer
Three key features
This riddle was solved by researchers using a computer analysis. It turned out that there seem to be three key elements common to all promising candidates. First, the active ingredient must be an amine in a particular configuration. Second, the substance should be firm rather than labile so it does not stay in the porin tissues. Third, it should have a low globularity. "That means simply speaking, it has to have a rather flat and not a spherical structure, " the team writes.
How determined are the guidelines for the search for suitable drugs, tested Hergenrother and his colleagues by means of an experiment: They tried to convert a compound active against Gram-positive bacteria that it is also active against Gram-negative pathogens such as Escherichia coli.
Their choice was deoxynybomycin (DNM) - a substance that can kill off gram-positive bacteria and, in addition, already meets two of the three criteria required. Only the amine is missing from the molecule. For their experiment, the researchers added the required amino group of the compound in the correct position and put the sample to the test - with success. The new substance "6DNM-Amin" was also active against Gram-negative bacteria, making it a potential broad-spectrum antibiotic.
Only a waypoint
The decisive factor for the scientists, however, is not the creation of this new connection: "Whether it is at all well suited for use in humans still has to be demonstrated, " says Hergenrother. "What is more important is that we now understand the mechanisms and how we can make connections that are likely to get inside the pathogens."
However, this is only the first milestone on the way to becoming an effective antibiotic. Because only a drug that can penetrate into the cell interior, while potentially a good drug. But not all molecules with this ability are really active against the bacteria. According to the researchers, only about one out of every 200 randomly selected compounds that can penetrate into a gram-negative germ can do so. "But those are probabilities that you can work with, " concludes Hergenrother. (Nature, 2017; doi: 10.1038 / nature22308)
(University of Illinois, May 11, 2017 - DAL)