The first in half a century
A new antibiotic has been developed to fight gram-negative bacteria
Anna Kaznadzei, N+1
Scientists from the University of Illinois for the first time in the last fifty years managed to create a compound that will serve as the basis for a new line of antibiotics against gram-negative bacteria. The key parameters of such a molecule were its size, globularity, a certain balance of polar and hydrophobic characteristics and the presence of a rotating amine group that allows it to effectively penetrate into the cell through the pores. The compound created on the basis of dioxinibomycin has shown its effectiveness against a wide range of gram-negative bacteria. The study is published in Nature (Richter et al., Predictive compound accumulation rules yield a broad-spectrum antibiotic).
Gram-negative bacteria, unlike gram-positive ones, have two cell membranes. The outer membrane contains a lot of lipopolysaccharides, and the access of many substances to the cell is difficult because of this. There are much fewer antibiotics that would make it possible to fight this group of organisms compared to medications against gram-positive bacteria. The last group of such antibiotics was discovered in 1968. These are aromatic compounds called quinolones, and they are able to penetrate into a gram–negative bacterial cell through special protein complexes from the outer membrane - porins, through which the bacterium receives the substances necessary for its vital activity. Inside the cell, they block the mechanisms of DNA replication, and the bacterium dies.
Pathogenic bacteria are able to acquire resistance to antibiotics, so the development of new drugs is constantly required to combat them. In 2007, as part of the GlaxoSmithKline pharmacological project, five hundred thousand candidates for the role of a new antibiotic for gram-negative bacteria were analyzed, but the work was not crowned with success.
In this project, scientists have selected one hundred compounds with a potential antibiotic effect. The starting material for the development of new compounds were molecules that could, according to their spatial parameters, get inside a bacterial cell, and had antibiotic properties. At the same time, those of them were selected that could be subjected to various chemical transformations without serious difficulties, allowing them to slightly modify their polarity, spatial characteristics and other parameters.
An antibiotic acting on gram-negative bacteria, firstly, must pass through the pores, that is, be "recognized" by them, and secondly, it must have a sufficiently rigid structure and low globularity - that is, it must be characterized by a certain compactness so as not to get stuck there. In previous studies, it was shown that a compound that can pass through pores must have a high polarity and a mass of less than 600 Da. In addition, it must accumulate quickly in the cell, because gradient pumps will pump it out of there, and its rate of entry must exceed the pumping rate.
Computer modeling of the spatial structure of compounds and subsequent laboratory testing made it possible to compile a list of necessary criteria necessary for such a substance to successfully penetrate the cell. It turned out that compounds that have five or fewer rotating bonds, the globularity coefficient of which is 0.25 or less, accumulate most effectively in the cell, and in addition, they must, in addition to polar characteristics, have some hydrophobicity and have a sterically free (not fixed) amine group.
As a result, the compound dioxinibomycin (DNM) was chosen as the basis, which inhibits the DNA gyrase of gram-positive bacteria, but does not act on gram-negative species. It was first developed there – at the University of Illinois, but in 1960. Its globularity coefficient is 0.02, and it has no rotating bonds. Its analog having a six-membered ring instead of a five-membered one (6DNM) was modified by adding an amine group (6DNM-NH3) to it.
6DNM-NH3 structure. Drawing from the press release of the Antibiotic breakthrough:
Team discovers how to overcome gram-negative bacterial defenses – VM.
The resulting compound had antibacterial activity, effectively destroying almost all gram–negative bacteria involved in the experiment, including the extremely antibiotic-resistant pathogenic strain Escherichia coli ATCC BAA-2469 (the exception was the species Pseudomonas aeruginosa, which is also almost insensitive to antibiotics).
We have already told a lot about the difficulties in the development of antibacterial drugs faced by researchers before. The parameters selected by scientists for 6DNM-NH3 can serve as the basis for the development of a new line of antibiotics needed to combat a number of bacterial diseases. Scientists note that in previous projects, despite the huge variety of compounds proposed as candidate antibiotics for gram-negative bacteria, there were no molecules combining all the characteristics found in this study that are necessary for the effective passage of the substance through the pores and accumulation inside the cell.
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15.05.2017