A new study highlights the potential of random mixtures of antimicrobial peptides to significantly reduce the risk of resistance development compared to single peptides. These findings highlight the need for innovative solutions to overcome bacterial resistance and protect public health
Antibiotics are an essential tool in modern medicine, and are regularly used to treat bacterial infections and to prevent infections during surgeries. However, the widespread use of antibiotics has led to the development of resistance among many bacteria, which poses a significant threat to public health. A study recently published in PLOS Biology, led by Prof. Zvi Hioka from the Institute of Biochemistry, Food and Nutrition Sciences in the Faculty of Agriculture, Food and Environment at the Hebrew University of Jerusalem, and Prof. Jens Rolf from the Free University of Berlin, together with a post-doctoral researcher, Dr. Bernardo Antones, who was associated with both the Hebrew University and the Free University of Berlin, highlights the urgent need for new strategies to control bacterial infections following the growing threat of antibiotic-resistant pathogens. Correct use of antibiotics, rapid diagnosis, and careful development of new antimicrobial agents—preferably ones that are less likely to select for resistance compared to existing antibiotics—are critical.
Antibiotic resistance is emerging as an urgent global health challenge. Although people themselves do not become resistant to antibiotics, the bacteria that cause infections can develop this resistance, leading to diseases that are more difficult to treat. Recent figures from the World Health Organization highlight the seriousness of the issue, with reports of resistance rates of up to 42% for common bacterial strains in some countries. In the United States, the Centers for Disease Control and Prevention estimates that over 2 million antibiotic-resistant infections occur each year, underscoring the urgency of addressing this crisis.
The study examined whether random mixtures of antimicrobial peptides can significantly reduce the risk of developing resistance compared to antimicrobial peptides with only one sequence. The research team used the pathogenic bacterium *Pseudomonas aeruginosa*, a model of a gram-negative bacterium, known for challenging infections due to its inherent resistance to many types of drugs and its ability to form biofilms.
*Pseudomonas aeruginosa* developed experimentally in the presence of antimicrobial peptides or random mixtures of antimicrobial peptides, in order to evaluate the development of resistance and cross-resistance between the different treatments. The study also examined the adaptive costs of resistance on bacterial growth and the use of whole genome sequencing to identify mutations responsible for resistance. In addition, changes in the pharmacodynamics of the bacterial strains that developed were examined.
The findings indicate that random mixtures of antimicrobial peptides pose a much lower risk of developing resistance compared to individual antimicrobial peptides and mainly prevent cross-resistance to other treatments, while maintaining or improving drug sensitivity. Prof. Zvi Hioka emphasized the importance of their work, saying: "The growing threat of antibiotic-resistant bacteria requires innovative solutions. Our research on random mixtures of antimicrobial peptides offers a promising approach to overcome bacterial resistance, and offers a viable alternative to traditional antibiotics, thereby protecting public health."
The bacterium recognizes the peptides but does not develop resistance
The study indicates that *Pseudomonas aeruginosa* can recognize these antimicrobial agents, but fails to develop effective resistance within 4 weeks under laboratory conditions. In addition, these antimicrobial peptide mixtures are inexpensive to synthesize, have been shown to be non-toxic and non-hemolytic in a mouse model, with a strong efficacy profile in several models of human pathogenic bacterial infections.
The findings support the use of random mixtures of antimicrobial peptides over individual peptides, as resistance has developed in the laboratory against individual peptides. Although some antibiotics, such as teixobactin, were first thought to be "resistant to resistance," this was later disproved, necessitating caution even with the promising results of the random peptide mixtures. Research should be continued to examine the interaction of the random peptide mixtures with the host's immune system. Using peptides that integrate with the host's immune response can reduce dosage requirements and side effects. This approach may be a cost-effective method for reducing bacterial load and preventing resistance.
"It will still take a long time before we are ready for practical applications," said Prof. Jens Rolf. "However, our current work demonstrates the potential these combinations have when it comes to reducing antimicrobial resistance."
Alongside their active research, Prof. Zvi Chioka founded a company, in collaboration with the technology transfer company of the Hebrew University, called Profital, dedicated to the treatment of antibiotic resistance through innovative solutions - Pepticore. The company aims to develop and commercialize new antimicrobial agents that are less likely to select for resistance. Their approach involves using different combinations of antibiotics and testing mixtures made up of millions of molecules to prevent resistance. This initiative is essential, as antibiotic-resistant pathogens cause approximately 5 million deaths each year. Despite advances in diagnosis and careful antibiotic prescribing, the development of new drugs remains essential in the fight against increasingly resistant bacteria.
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