Antimicrobial peptides have not typically lived up to their promise, especially when it comes to beating antibiotic resistance, but novel avenues could see them reach the clinic yet.
The story of antimicrobial peptides , particularly in tackling antibiotic resistance , has been one of false dawns and unfulfilled promises. But perhaps a new generation of “smarter” compounds could see them find a wider role in clinical practice, said experts.
AMPs may be small molecules, consisting of short chains of amino acids, but these naturally occurring compounds have an important function: They are the “frontline defense” against invasive bacteria, said Henrik Franzyk, MSc Engineering, associate professor in the Department of Drug Design and Pharmacology at the University of Copenhagen, Copenhagen, Denmark.AMPs are cationic, meaning they are positively charged. “The reason why nature has maintained these molecules is that all the microbes out there have a negative surface charge,” explained Hans-Georg Sahl, PhD, emeritus professor of pharmaceutical microbiology at the University of Bonn, Bonn, Germany.While AMPs are also hydrophobic, they are often amphipathic, with both hydrophobic and hydrophilic regions that allow them to target cell membranes and cause them to rupture similarly to how detergent acts. “Thus, the content of a cell gets released, and it destroys the pathogen,” explained Paulina Szymczak, a PhD candidate in the Institute of AI for Health at Helmholtz Munich, Neuherberg, Germany.“There are variations of that theme,” said Eefjan Breukink, PhD, professor of microbial membranes and antibiotics at Utrecht University, Utrecht, the Netherlands. “And then it depends on the sequence of the particular peptide,” as some can cross the cell membrane and damage the bacterium internally. Szymczak explained that AMPs can, in this way, target the cell DNA, as both the membrane and the DNA are negatively charged. “That’s also what makes them so powerful because they don’t have just one mechanism of action, as opposed to conventional antibiotics.” But they also have another crucial function. They activate the innate immune system via so-called resident immune cells that are “sitting in the tissues and waiting for bacteria to turn up,” explained Franzyk. “The problem with antibodies is that they typically need to replicate,” he continued, which takes between 4 and 7 days — a timeline that is much better suited to tackling a viral infection. Bacteria, on the other hand, have a replication cycle of just 30 minutes.“But the human body is clever in that it only produces these antimicrobial peptides where the bacteria are, so they are not circulating in the blood,” said Franzyk. If a small part of tissue becomes infected, the innate immune cells start producing AMPs, which may kill the bacteria, or call on other immune cells to help. As part of this process, “they will also kill part of our own tissue, but that’s the price we have to pay,” he said.It is this aspect that has, so far, limited the use of AMPs in clinical practice, certainly as a replacement for conventional antibiotics limited by bacterial resistance. The trials conducted so far have been, by and large, negative, which has dampened enthusiasm and led to the perception that the risk they pose is too great for large-scale investment.AMPs “are not made for what we need from antibiotics in the first place,” explained Sahl. “That is, a nice, easy distribution in the body, going into abscesses” and throughout the tissues. He continued that AMPs are “more about controlling the flora in our bodies,” and they are “really not made for being used systemically.” Szymczak and her colleagues are now working on designing active peptides with a strong antibacterial profile but limited toxicity for systematic use. However, the “downside with these peptides is that they are not orally available, so you can’t take a pill,” Breukink said, but instead they need to be administered intravenously. There are, nevertheless, some antibiotics in clinical use that have the same molecular features as AMPs. These include colistin, a last-resort treatment for multidrug-resistant gram-negative bacteria, and daptomycin, which is used in the treatment of systemic infections caused by gram-positive species. Szymczak added that there have been successes in using AMPs in a more targeted way, such as using a topical cream. Another potentially promising avenue is lung infections, which are being studied in mouse models.Crucially, AMPs are markedly less prone to bacterial resistance than conventional antibiotics, partly due to their typical target: The cell membrane.“Biologically and evolutionarily, it is a very costly operation to rebuild the membrane and change its charge,” Szymczak explained. “It’s quite hard for bacteria to learn this because it’s not a single protein that you have to mutate but the whole membrane.” This is seen in the laboratory, where it takes around five generations, or passages, for bacteria to develop resistance when grown in the presence of antibiotics, but up to 40 passages when cultured with an AMP. The limits of the ability of AMPs to withstand the development of bacterial resistance have been tested in the real world. Colistin has been used widely in Asia as a growth promoter, especially in pig farming. Franzyk explained that farmers have used enormous quantities of this AMP-based antibiotic, which has indeed led to the development of resistance, including contamination of meat for human consumption, leading to resistance spreading to other parts of the world. “The bad thing about this is it’s not something each individual bacteria needs to acquire,” he said. Because resistance is stored on small, cyclic DNA called plasmids, it “can be transferred from one bacterial species to another.”Franzyk suggested that AMPs could nevertheless be used in combination with, or to modify, existing antibiotics to revitalize those for which there is already bacterial resistance, or to allow antibiotics that ordinarily target only gram-positive bacteria to also treat gram-negative infections, for example. Szymczak and her colleagues are using artificial intelligence to design novel AMP candidates. Instead of manually going through compounds and checking their activity profiles in the lab, those steps are carried out computationally “so that, in the end, you synthesize as few candidates as possible” and can proceed to a mouse model “as fast as possible.” She personally is looking at the issue of strain-specific activity to design a compound that would target, for example, only multidrug-resistant strains. “What we can do now is something that will target everything, so a kind of last resort peptide. But we are trying to make them smarter in their targets.” Szymczak also pointed out that cancer cells are “negatively charged, similarly to bacterial cells, as opposed to mammalian cells, which are neutral.” “So in theory, maybe we could design something that will target cancer cells but not our host cells, and that would be extremely exciting.” However, she underlined that, first, they are trying to tackle antimicrobial resistance before looking at other spaces. Finally, Breukink is screening for small antibacterial compounds in fungi that are around half the size of a normal peptide and more hydrophobic, meaning there is a much greater chance of them being orally available. But “you first have to test, of course,” he said, as “if you don’t have specific targets, then you will get problems with toxicity, or other issues that you do not foresee.” Liam Andrew Davenport is a medical reporter with more than 20 years of experience covering a wide range of specialties and topics in the field.All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC. This website also contains material copyrighted by 3rd parties.
Europe European Drug Development Drug Discovery Drug Pipeline Drug Development Pipeline Bacteria Bacterial Infection Microbicides Antimicrobials Gram-Negative Bacteria Gram Negative Bacterial Infections Gram-Positive Bacteria Gram Positive Bacterial Infections Antimicrobial Resistance Resistance To Antimicrobials Tissue Antibiotic Resistance Resistance To Antibiotics
United States Latest News, United States Headlines
Similar News:You can also read news stories similar to this one that we have collected from other news sources.
New hope for the Sixers | Sports Daily NewsletterJoel Embiid is set to make his season debut against the Knicks.
Read more »
Protein degradation strategy offers new hope in cancer therapyA team of scientists has used a novel approach to identify protein degraders that target Pin1, a protein involved in pancreatic cancer development.
Read more »
Niles: New parks provide new hope for theme park fansUniversal Epic Universe will open in May, with BON Luxury Theme Park in Mexico debuting the following year.
Read more »
Canada Takes One Health Approach to Antimicrobial ResistanceCanadian researchers are collaborating across disciplines to find new solutions to antimicrobial resistance.
Read more »
The 10 Best Skincare Products With Copper PeptidesFrom serums to eye masks, we've rounded up the best products with copper peptides to shop now and reap their firming, collagen-promoting benefits later.
Read more »
Ulcerative Colitis: New Medications, New Hope for RemissionSeveral new drugs will soon be available that show greater effectiveness at treating -- and possible ending -- ulcerative colitis.
Read more »