【PNAS】Great prospect - new drug candidates are discovered in bacteria, which are expected to be used as antibiotics!

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Author: Ashley Introduction: Bacteria show great promise as a source of active ingredients
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Using computer-based genome analysis, researchers at ETH Zurich have now discovered a new class of natural products that could one day be used as antibiotics
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Animals, plants, fungi and bacteria - each organism carries a whole host of compounds that enable it to interact with its environment, attract a mate or deter an enemy
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Bacteria are one of the oldest life forms on Earth and contain many complex chemical structures that have accumulated over millions of years of evolution
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Many of these metabolites have been shown to be highly effective as active ingredients in human medicine
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In fact, about one-third of drugs approved today are derived from natural products
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This includes most antibiotics
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However, unlocking the chemical mysteries of bacteria is not so easy
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The hurdle is that many types of bacteria are difficult to grow in the lab
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And often, only in tandem with other organisms do they produce natural products of medical interest
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The application of bioinformatics and modern DNA sequencing methods can significantly speed up the search for new active ingredients
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Using this method, a research team led by Jörn Piel, Professor of Microbial Interactions at ETH Zurich, has now discovered a new synthetic pathway for peptide-like natural products that appears to be widespread in bacteria
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Their findings were recently published in Proceedings of the National Academy of Sciences of the United States of America (PNAS), titled "Ribosomally derived lipopeptides containing distinct fatty acyl moieties
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"
Narrowing Your Choices It was by combing through a vast digital library of bacterial genomes that researchers discovered what they were looking for
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First, they looked for blueprints for peptides -- small protein molecules, and then for blueprints for enzymes that could modify those peptides
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Modification of these enzymes produces complex natural products in bacteria; many of these products display specific activities or additional stability
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Because of the characteristic patterns of peptide blueprints, the researchers were able to use search algorithms to find them
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Blueprints for these peptide natural products are stored in the genome in compact form
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Next to this peptide gene is the gene for the enzyme
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"These enzymes function in very different ways, meaning that natural peptide products have great potential to deliver new active ingredients," explains Florian Hubrich, one of the lead authors of the study
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"From blueprint to natural product genome analysis showed that these enzymes are The key to discovering a new class of natural products
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Researchers group similar candidates according to blueprints of different enzyme types
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In the process, they realized that in one of the largest groups, the function of the enzyme was still unknown
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For three potential natural products in this population, the researchers then performed laboratory tests to validate the computer predictions
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To do this, they inserted the relevant genes into laboratory bacteria and analyzed what the microbes actually produced
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Members that led to the discovery of this new class of natural products are cyclic peptide molecules with fatty acid appendages
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Certain lipopeptides (peptides linked to fatty acids) are known to be active ingredients
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For example, the antibiotic daptomycin has a very similar structure
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However, the biotechnological processes required to produce the drug are still very complex
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This is because antibiotic-producing bacteria also produce several natural product variants, each with fatty acids of different lengths
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Only one of these variants is used as a drug, which must then be purified from bacterial cells using a complex process
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It was here that Piel saw the greatest benefit of this new class of natural products
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New candidate antibiotics remain to be tested.
Daptomycin and other lipopeptides are assembled from amino acids of biological origin through giant enzymes specialized in this process
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These giant enzymes are not easy to use for genetic engineering purposes
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In contrast, a new class of peptide-like natural products is easier to produce—in a process based on genetically modified bacteria
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Moreover, this method can also be used to generate new natural product variants
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In just a few steps, the researchers were able to modify the blueprints of these natural products in order to create "custom" active ingredients
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For example, the sequence of amino acids in the peptide backbone can be modified by means of corresponding genetic mutations
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Furthermore, this macro-level genomic analysis has identified a number of novel enzyme candidates that can be combined with peptide genes on a modular basis
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This study describes a total of three enzymes that attach fatty acids of different chain lengths to peptides
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Anna Vagstad, the study's other lead author, said: "Initial experiments showed that it is indeed possible to generate these tailored lipopeptides in the laboratory
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" The next step will be to study the biological activity of this new class of substances
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"Financial incentives for pharmaceutical companies to develop new antibiotics are often low, but we researchers can at least take the first step, which is to find new active ingredients
," Vagstad said.

Reference: https://phys.
org/news/ 2022-02-drug-candidates-bacteria.
htmlNote: This article is intended to introduce the progress of medical research and cannot be used as a reference for treatment plans
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For health guidance, please go to a regular hospital for treatment
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