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The discovery of penicillin in 1928 by Alexander Fleming was a momentous moment in the world of healthcare, eventually leading to the development of antibiotic drugs that allowed physicians to treat illnesses and infections that were once severe and life-threatening. But our reliance on antibiotics has now led to an emerging global health problem in the form of antimicrobial resistance, resulting in the need to once again find new treatments to help fight off potentially deadly infections. Antimicrobial resistance occurs when bacteria, viruses, fungi and parasites evolve over time and stop responding to medicines normally used to treat them. The result of this is that infections become more difficult to treat, increasing the risk of disease spread, severe illness and death. Misuse and overuse of antimicrobial drugs, such as antibiotics, are the other main factors in the development of drug-resistant pathogens. The World Health Organization (WHO) listed antimicrobial resistance as one of the top 10 global public health threats facing humanity, and it is predicted to cause around 10 million deaths per year by 2050. As such, there has been an increased focus on the development of new antimicrobial agents, with antimicrobial peptides (AMPs) - a class of small peptides that widely exist in nature - emerging as one of the most promising solutions to potentially tackle antimicrobial resistance. What are antimicrobial peptides and how can they be used to tackle antibiotic resistance? Fleming didn’t just discover penicillin; he also discovered the antibacterial properties of lysozyme - the first natural antibiotic isolated from the human body - in 1922. Since then, numerous types of molecules showing antimicrobial activity have been isolated from animals, plants, insects and bacteria. Eukaryotic AMPs, which describes antimicrobial peptides that are derived from organisms whose cells have a nucleus, became a focus area of research in the mid-20th century, and there are now more than 3,000 AMPs reported in the Antimicrobial Peptide Database (APD) originating from six life kingdoms; animals, plants, fungi, protists, archaea, and bacteria. But what exactly are antimicrobial peptides? Also known as host defense peptides, antimicrobial peptides are small, naturally-occurring molecules that play an important role in the innate immune response of virtually all living organisms, providing a wide range of inhibitory effects against bacteria, fungi, parasites and viruses. The mechanism of action (MOA) of antimicrobial peptides has been extensively studied since they were discovered, and it’s their multifaceted MOA that potentially makes them such a promising alternative to traditional antibiotics, particularly when it comes to tackling multi-drug resistant pathogens. “The use of AMPs as an active antibacterial component is appealing due to their low potential to induce new types of resistance, which can be attributed to their multifaceted mode of action. AMPs interact with the bacterial cell wall and have a broad-spectrum effect on both gram-positive and gram-negative bacteria. Furthermore, they are effective against antibiotic-resistant bacteria, making them a valuable tool in preventing and treating infections caused by such bacteria,” explained Martin Andersson, professor at the Department of Chemistry and Chemical Engineering at Chalmers University of Technology. Generally, antimicrobial peptides use two broad MOAs to target bacteria and kill them. In the first MOA, antimicrobial peptides induce membrane disruption, resulting in cell lysis and death, while in the second, antimicrobial peptides enter cells without membrane disruption and inhibit essential intracellular function, binding to nucleic acids or intracellular proteins. Andersson said he believes antimicrobial peptides have the potential to become vital components in the battle against antimicrobial resistance. “Overall, AMPs have the potential to replace traditional antibiotics and treat infections that are currently untreatable. This approach is critical in combating antimicrobial resistance, which is fueled by the inappropriate use and overuse of antibiotics,” he commented. Furthermore, studies have shown that some antimicrobial peptides and conventional antibiotics have synergistic effects, meaning antimicrobial peptides and antibiotics could also be used in combination to kill drug-resistant bacteria, prevent drug resistance, and ultimately improve the therapeutic effects of antibiotics. Progress toward creating AMP-based therapies Despite the promising potential of antimicrobial peptides to combat antimicrobial resistance, creating a wide variety of AMP-based therapies can be challenging. This is because antimicrobial peptides generally have a short half-life and break down rapidly when they encounter bodily fluids, such as blood. They can also be costly to produce. However, efforts to create product candidates from antimicrobial peptides are expected to accelerate in the coming years thanks to an improved understanding of the MOA of antimicrobial peptides, innovative formulation strategies, and advanced chemical synthesis protocols to lower manufacturing costs. Moreover, some antimicrobial peptides are currently undergoing preclinical and clinical trials, and there have been some recent research projects in particular that have shown promising results, including the development of a new antibacterial material used as a wound spray, and the creation of a new type of antibiotic that can be rapidly modified to overcome future resistance. The wound spray was developed by researchers at Chalmers University of Technology in Sweden. Andersson was head of research for the study and said that the spray is a suspension of particles in water, which consist of a hydrogel that contains chemically attached antimicrobial peptides, representing an advancement from a previous wound dressing material that was made in sheet form from a similar material. “The spray's active ingredients, the particles, can penetrate deeper into the wound bed, thereby enhancing the accessibility of the material to the bacteria in the wound. For the particles to be effective, they must come into physical contact with the bacteria, as they function as a contact-killing material. The spray was developed in response to requests from physicians seeking a more effective wound treatment option,” said Andersson. The new material developed for the spray has been shown to be effective against many different types of bacteria, including antibiotic-resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), and has the potential to prevent infections, in turn reducing the need for antibiotics. “The spray has the potential to be used in any setting where bacterial growth is undesirable, particularly in environments where human cells are present, as the particles are non-toxic to our cells,” said Andersson. Meanwhile, scientists at RMIT University recently created a new type of antibiotic called priscilicidin - derived from indolicidin, a natural antibiotic found in cows’ immune systems - that has a simple design, allowing it to be produced quickly and cost-effectively in a lab. It can also be tailored to tackle different types of antimicrobial resistance. “Priscilicidin is a very short peptide that we rationally designed from natural antimicrobial motifs and synthetic gelling motifs. Thanks to its very short molecular size, it is easy and cost-effective to produce. Its molecular structure can also be easily modified to overcome future resistance, optimize activity to microbial strains and to adapt viscosity to applications,” explained Céline Valéry, senior lecturer in pharmaceutical sciences at RMIT University and principal supervisor of the study. According to Valéry, priscilicidin was shown to be very active against Candida fungal strains, including a resistant strain. For this reason, the research team’s initial focus will be on the preclinical development of priscilicidin-based therapies against fungal infections. Moving away from therapies, another promising tool in the antimicrobial peptide research field is an AI-powered AMP prediction model developed by researchers from the Gwangju Institute of Science and Technology (GIST) in South Korea. Named AMP-BERT, the tool is a classification system that uses AI-based bidirectional encoder representation from transformers (BERT) architecture that improves upon current AMP classification models. AMP-BERT is able to capture the functional and structural properties of peptides and classify them as either AMPs or non-AMPs, allowing it to make better classifications even with external data. This improved classification system could potentially help the development and discovery of AMP-based drug candidates and therapies. “As more AMPs are experimentally validated and new structural information is uncovered using computational methods, we will be able to make more effective antibiotic drugs and potentially stop a new pandemic from spreading across the world in near future,” said Hojung Nam, who led the study along with Hansol Lee. Research on antimicrobial peptides is continuously developing, and with recent advancements in technology and an enhanced understanding of the MOA of antimicrobial peptides, it’s likely that further progress will be made in developing more and more AMP candidates in the coming years, with the antimicrobial peptide market expected to be worth around $539.32 million by 2027. “While there is still much research needed to fully optimize the use of AMPs as antimicrobial agents, I think it is likely that we will see more AMP-based drugs and therapies become available in the future,” said Valéry.

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