The Future of Antibiotics: Engineering Microbial ‘Factories’ to Combat Resistance
Comparing molecules to cars might seem a stretch, but when it comes to their production, there are striking similarities. Some are, in fact, produced within a cell like on an assembly line.
Helge Bode and Tobias Erb of the Max Planck Institute for Terrestrial Microbiology in Marburg are working to rebuild these molecular production lines to create new antibiotics, urgently needed in the fight against resistant pathogens.
The Growing Threat of Antibiotic Resistance
Even a common middle ear infection can now be fatal, as many bacteria that cause such infections are now resistant to antibiotics. And resistance is increasing: experts at the World Health Organization (WHO) predict that as many as ten million people could die each year from multi-resistant germs by 2050.
This creates a significant require for new antibiotics. More and more pathogens are becoming immune to proven drugs, often due to their careless employ. The development of new antibiotics is not necessarily longer or more complex than that of other drugs, but We see less lucrative for the pharmaceutical industry.
Harnessing the Power of Microbial Metabolites
Bode and Erb are therefore seeking a new way to produce antibiotics and other medical compounds, starting with the substances that microorganisms themselves produce. Bacteria, for example, produce a wealth of substances in their cells that perform vital functions in metabolism, communication with other cells, or defense against competitors. Many of these substances are peptides, which consist of chains of amino acids, but are shorter than proteins.
Their versatility makes them ideal for use in medicine and industry. Peptides are the basis for the antibiotic penicillin, the cancer drug romidepsin, or the immunosuppressant ciclosporin. Approximately 60 percent of all therapeutics currently used in human medicine are based on biomolecules produced by bacteria and fungi.
From Natural Compounds to Novel Designs
The scientists in Marburg aim to tap into this vast reservoir of naturally occurring peptides, equip them for new tasks, and, inspired by nature, develop entirely new peptides. “Unlike molecules produced in the lab without a natural template, we can assume that peptides from nature have a specific function or effect. Otherwise, evolution would have eliminated them long ago,” explains Helge Bode, Director at the Max Planck Institute for Terrestrial Microbiology.
For Bode and Erb, similarly a Director at the institute, bacteria and fungi represent a virtually inexhaustible reservoir of new active ingredients. “Bacteria and other microbes were on Earth for two billion years before the first cells with a nucleus arose. They therefore had enough time to produce new molecules for a wide variety of purposes,” says Tobias Erb.
Improving on Nature’s Designs
However, evolution doesn’t always find the optimal solution, or it may have to meet multiple requirements and therefore compromise on the effectiveness of a peptide. The two directors at the Max Planck Institute in Marburg therefore aim to optimize already known peptides. For medical use in humans, they must not only be effective but also distribute quickly and evenly throughout the body, remain available for a long time and be well tolerated.
They are also designing entirely new molecules. Since despite the diversity of peptides produced by microorganisms, there are countless molecules that nature has not yet invented – and may never invent. “Evolution is rather conservative,” says Erb. “It usually relies on what has been tried and tested, and rarely does anything completely new emerge.”
The scientists around Helge Bode and Tobias are much more progressive: they aim for to produce all peptides from all theoretically possible building blocks and then select those that reach into question as drugs or raw materials for industry. To gain ideas for new peptides, Bode and Erb analyze the natural production processes and functions of the molecules in bacteria and fungi.
The Power of Synthetic Biology and AI
The proteins of a cell, as well as most of its peptides, are produced with the help of specialized molecular machines, the ribosomes. The peptides produced in this way consist of 20 different amino acids with a specific spatial structure, the so-called L-amino acids. These can be combined in a variety of ways. There are already more possible combinations for peptides with lengths of 40 to 50 amino acids than there are atoms in the entire solar system. How can new, antibiotic-effective peptides be found in this vast diversity? Tobias Erb uses artificial intelligence for this purpose, which he trains with known peptides to find new antimicrobial peptides. “It works like an AI learning to write crime novels based on a few dozen Sherlock Holmes stories – only our AI is trained with thousands of variants,” says Erb.
Enzyme Engineering: Building Peptide ‘Assembly Lines’
Helge Bode, is interested in peptides that are not produced in ribosomes. “They also contain other amino acids, such as the mirror images of the L-amino acids, the D-amino acids, or those that have been further modified,” explains Bode. These peptides are synthesized by special enzymes, the so-called non-ribosomal peptide synthetases. They function as catalysts for chemical reactions that join one amino acid to a peptide.
“A synthetase works according to the same principle as an assembly line in the automotive industry,” explains Helge Bode. “Selection, activation, linking and modification of the components take place at different modules of the enzyme. Each module is therefore like a single robot station in the factory for a specific production step.”
The trick is that the modules can be separated from each other and assembled into a new enzyme, which then produces a different peptide. And two enzymes can be coupled together. “We are not only exchanging individual stations, but switching two assembly lines one after the other. That’s like a car starting as a VW and then continuing to be built as a Tesla,” says Bode. “We can also incorporate parts from BMW, Mercedes or Volvo.”
Cell-Free Production for Rapid Prototyping
To produce the amount of a peptide needed for further investigation, researchers usually equip bacteria with the corresponding gene. The cells then produce the desired molecule in addition to their own molecules. However, this becomes problematic when producing an antibiotic, whose job is to kill bacterial cells. Antibiotics can therefore often only be produced in bacterial cells with tricks such as a very efficient transport out of the cell or in the form of an inactive precursor.
Tobias Erb and his team have therefore developed a production process that does not require living cells. “It is a cell-free transcription-translation system that can produce a peptide from its DNA blueprint within hours. This allows us to produce and analyze several hundred peptides per day, faster and more cost-effectively than any other chemical or biological production method,” explains Erb.
This allows the researchers to quickly gain new data, which can then be analyzed with the help of AI. The team led by Tobias Erb uses the fully automated laboratory MaxGenesys, which was built in Marburg in the last three years with funds from the Max Planck Foundation, for these cycles of production, analysis and data interpretation.
A Collaborative Approach to Drug Discovery
Helge Bode and his group are now also developing a process for the large group of structurally more complex non-ribosomal peptides, which can be produced without cells within hours instead of days – and in quantities that allow for a precise analysis of the substances. Together with the Compound Management and Screening Center of the Max Planck Society in Dortmund, it is then investigated whether a peptide is fatal for different pathogens, can kill cancer cells and whether it harms healthy human body cells.
Helge Bode and Tobias Erb witness their scientific approach as being in a long tradition: “Humanity has always been inspired by nature, but then adapted the technology to its own needs,” says Erb. “Airplanes, for example, use their wings like birds to generate lift. But they don’t have feathers and aren’t movable. Only in this way do they give humans the ability to overcome gravity.” The design of new peptides is therefore based on inspiration rather than imitation.
FAQ
Q: What is antibiotic resistance?
A: Antibiotic resistance occurs when bacteria evolve to survive exposure to antibiotics, rendering the drugs ineffective.
Q: What are peptides?
A: Peptides are short chains of amino acids that can have a variety of biological activities, making them promising candidates for new drugs.
Q: How are researchers using AI in this process?
A: Artificial intelligence is being used to analyze vast datasets of peptides and predict new antimicrobial compounds.
Q: What is non-ribosomal peptide synthesis?
A: This is a process used by bacteria and fungi to create peptides using enzymes instead of ribosomes, allowing for the creation of more diverse molecules.
Q: What is cell-free production?
A: This method allows for the production of peptides without the need for living cells, speeding up the research process.
Did you know? The number of possible peptide combinations for even a relatively short chain of 40-50 amino acids exceeds the number of atoms in our solar system!
Pro Tip: Understanding the mechanisms of antibiotic resistance is crucial for developing effective strategies to combat it. Stay informed about the latest research and public health recommendations.
Want to learn more about the fight against antibiotic resistance? Explore the World Health Organization’s resources.
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