Antibiotics don't smell
Bioinformatics found 79 candidates for the role of new antibiotics in human feces
St. Petersburg State University Press Service
An international group of scientists led by Pavel Pevsner, head of the laboratory "Center for Algorithmic Biotechnology" of St. Petersburg State University, has created a new computational method for searching for cyclopeptides – a class of substances that includes many well-known antibiotics. Using an approach called CycloNovo, scientists analyzed the mass spectra of human stool samples and found 79 possible candidates for the role of a killer of bacteria there.
When we talk about antibiotics, first of all we think about medicines that can be bought at a pharmacy. However, antibiotics are primarily microscopic bullets that bacteria use to kill each other. People simply took and adapted some of these biologically active substances for their needs – fighting infections. Since a variety of microorganisms have the ability to produce such substances, the question arises: can the bacteria living in our intestines (which number up to a thousand different species) produce antibiotics?
In search of an answer to this question, an international group of scientists led by Pavel Pevsner, head of the laboratory "Center for Algorithmic Biotechnology" of St. Petersburg State University, professor at the University of California at San Diego (UCSD) and one of the leading experts in the field of bioinformatics, has created a new computational method for searching for cyclopeptides - a pharmacologically important class of substances, including many well–known antibiotics, antitumor compounds and immunosuppressants. The cyclic structure of such molecules, on the one hand, gives them important physicochemical properties that allow them to be used as medicines, and on the other hand, significantly complicates their detection in the natural samples studied by scientists.
Gramicidin C is one of the first antibiotics that, along with penicillin, began to be used to treat the wounded during World War II.
Gramicidin C is a typical representative of cyclopeptides, consisting of only five different amino acids, each of which is repeated twice in the cycle.
Starting with gramicidin C, discovered by Soviet scientists Georgy Gause and Maria Brazhnikova in 1942, only about 1,200 cyclopeptides have been found and described to date. The difficulties of detecting such substances and determining their structure lead to the fact that the work on the discovery of each new compound stretches for many years. The breakthroughs of recent years in the field of biotechnology and bioinformatics have brought us closer to the emergence of a much faster way to find previously unknown cyclopeptides. Thus, an article by Pevsner's group, recently published in the prestigious journal Cell Systems, describes more than 400 new cyclopeptides at once. To identify them, the team of scientists needed only a few days of work of their new algorithmic approach, called CycloNovo, on a computing cluster. During this time, a huge amount of experimental data was processed from samples of microbes and plants obtained earlier by other scientists and posted in open access in the hope of the emergence of appropriate processing algorithms.
CycloNovo analyzes the output data of modern high-precision mass spectrometers – extremely sensitive "molecular weights" that break up molecules into small fragments and measure their mass. By analyzing the masses of molecular fragments, CycloNovo determines which mass spectra correspond to cyclopeptides, rather than standard linear compounds, and then reveals their structure - the amino acid sequence. The whole procedure can be compared to finding a needle in a haystack. And despite the fact that such a computational task faced science more than ten years ago, it was only now possible to fully solve it. Curiously, the proposed algorithm resembles the approach used to solve the problem of genome assembly – a completely different field of bioinformatics, to which the Center for Algorithmic Biotechnology has also made a significant contribution.
The very first applications of CycloNovo to real data demonstrated its applied significance as a tool in the hands of biologists and have already managed to lead to medically interesting results. So, with the help of the program, the mass spectra of the obtained human stool samples were analyzed, which Professor Larry Smarr, one of the co-authors of the article, collected for four years. Unexpectedly, a large number of cyclopeptides were found in them, which are characteristic of flax seeds, and not at all bacteria that are part of the human microbiota. This fact, at first glance, calls into question the correctness of the algorithm and the entire study as a whole. However, it soon became clear that Smarr used flaxseed oil as part of his diet, and the days of use exactly coincide with the dates on which the corresponding samples were collected. Thus, for the first time it was clearly demonstrated that cyclopeptides from food can retain their structure when passing through the unfavorable environment of the human stomach and intestines. It is likely that cyclopeptides are the main factor explaining the antimicrobial activity of flax seeds. Another important result of this experiment was that the cyclopeptides of flax seeds are just a few representatives of 79 cyclopeptides found by CycloNovo in the stool samples under study. Determining their biological significance and functions is a separate task, which is already being worked on in collaboration with physicians and biologists. It is planned that various approaches to processing additional types of data obtained from the human microbiome will be added to the existing analysis.
In addition to Pavel Pevsner, young scientists of St. Petersburg State University Andrey Przybelsky and Alexey Gurevich participated in the work.
Alexey Gurevich, Head of Natural Products Discovery at the Center for Algorithmic Biotechnology: "An accurate and fast algorithm is the key to the success of a bioinformatic tool."
"However, this is not its only component. It is extremely important that the created program is easy to use. Only in this case it will be in demand by the scientific community and will bring real benefits. As in our previous projects to create tools for searching for antibiotics and other biologically active substances, we have made CycloNovo as convenient as possible even for scientists with a minimum level of computer literacy. The program can be launched literally in a couple of mouse clicks, and the results of the work can be viewed directly in your Internet browser, and you will not have to install anything else on your computer," notes Alexey Gurevich, Candidate of Physical and Mathematical Sciences and head of Natural Products Discovery at the Center for Algorithmic Biotechnology.
Together with Pevsner, Gurevich and Bahar Behsaz (UCSD graduate student), UCSD staff Fernando Vargas and Professor Larry Smarr, Professor Hossein Mohimani from Carnegie Mellon University (USA), as well as Dr. Joshua Milne and his graduate student Mark Fisher from University of Western Australia.
The project was financially supported by grants from the Russian Science Foundation, UCSD, the US National Institutes of Health, the Australian Research Council and The Australian Government.
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