The clout of “bad guys” can also be harnessed: researchers report that a notorious pathogen found in sugar cane could become the source of a new class of much-needed antibiotics. They have deciphered the sophisticated mechanism by which the plant pathogen's "battle agent" can kill bacteria that are dangerous to us. This could now pave the way for the development of antibiotics, against which "hospital germs" hardly develop any resistance, say the researchers.
One speaks of the “antibiotics crisis”: Medicine’s miracle weapons are increasingly losing their power – some bacterial pathogens have developed resistance to the common active ingredients. If you have been infected with such a resistant germ, there is a risk of death, because the medical possibilities are then approaching the level of more than 100 years ago. In the meantime, thousands of people fall victim to the stubborn pathogens every year. There is therefore an urgent need for alternative active ingredients to the previous antibiotics.
For some time now, research has focused on an active ingredient that comes from a surprising source: It is formed by the plant pathogen Xanthomonas albilineans, which causes so-called leaf streaks in sugar cane, which leads to major damage in cultivation. It is assumed that the pathogen uses the so-called albicidin to damage the plants and thus enable it to spread. In addition to its function in the development of leaf streaks, researchers also discovered a strong antibacterial effect when studying the active ingredient: solutions containing albicidin killed many germs that can cause diseases in humans.
How does albicidin work?
It has already become apparent that the effect is based on the disruption of an enzyme that only occurs in plants and bacteria. Humans and animals could thus be spared from treatment with the substance. However, the use of albicidin for the development of antibiotics has so far been hampered by the lack of clarity about how the active ingredient interferes with the bacterial enzyme system. As the international team with the participation of researchers from the TU Berlin now reports, advances in the technology of cryo-electron microscopy have made the decisive insights possible. By examining deep-frozen protein-DNA complexes, the scientists were able to visualize in detail the sophisticated mechanisms on which the albicidin effect is based.
As the researchers explain, the active ingredient is directed against a protein that is found in both plants and bacteria and is called DNA gyrase. This enzyme binds to DNA and twists it - a vital process for cells to function properly. In order to fulfill this task, the gyrase has to briefly cut through the DNA double helix. This is a tricky point because broken DNA would be lethal to cells. Normally, the gyrase quickly reassembles the two pieces of DNA during its work. It is precisely at this point that albicidin intervenes, as can now be seen from the icy insights into the microcosm.
Refined blockade with potential
It was found that the albicidin forms an L-form, which allows it to interact in a sophisticated way with both the gyrase and the DNA. In this state, the enzyme can no longer move to bring the DNA ends together, the scientists explain. According to them, the effect of albicidin is comparable to a bulky element that is clamped between two gears. "It was a great privilege to see how the molecule is bound to its target and how it works," says co-author Dmitry Ghilarov from the Jagiellonian University in Kraków and the John Innes Center in Norwich.
According to the researchers, an important aspect is that the mechanism of action of albicidin differs significantly from that of conventional antibiotics. Thus, the molecule and its derivatives could likely be effective against many of the current antibiotic-resistant bacteria. "Furthermore, because of the nature of the interaction, it stands to reason that albicidin makes it difficult for bacteria to develop resistance," says Ghilarov. "Now that we understand the structure, we can try to further exploit this binding pocket and further modify the substance to improve its potency and pharmacological properties," explains Ghilarov.
Here, too, the researchers can already point to successes: They were able to use their discoveries to chemically synthesize variants of the antibiotic with improved properties. In initial laboratory tests, they proved effective in low concentrations against some of the most dangerous bacterial pathogens. The team hopes to advance the research to human clinical trials soon. This could lead to the development of a new class of antibiotics, much needed given the global threat of antimicrobial resistance. "We think this is one of the most exciting new antibiotic candidates in many years," concludes Ghilarov.
Source: John Innes Centre, TU Berlin, specialist article: Nature Catalysis, doi: 10.1038/s41929-022-00904-1