Since early 2020, COVID-19 has demanded most of the world’s media attention in comparison to other global health challenges. However, one major global health concern has been overshadowed: steeply rising bacterial infection rates, which has been alarming and may have severe public health repercussions. This is largely due to the uncontrolled consumption of antibiotics and the subsequent development of “superbugs” or antimicrobial resistance (AMR), warranting an urgency to develop alternative therapeutic options.
One novel therapeutic option that our lab at the Indian Institute of Technology Ropar investigates is antibacterial peptide gels.
Why are superbugs of concern?
When a virus mutates, it can become either more infectious or more deadly. Similarly, the overuse of antibiotics is taking us on the path of increasing bacterial resistance or AMR, especially in hospital settings, where patients undergo implantation surgery and are exposed to pathogenic AMR bacteria. AMR infection in hospital settings could furthermore lead to repeated surgeries to remove the infection. This often results in unpleasant experiences for patients due to prolonged hospitalization, added cost to treatment, and in the worst cases implant rejection or amputation.
One recent report by Lancet highlights an alarming increase in casualties due to AMR globally. The study estimates that bacterial AMR contributed to 1.27 million deaths in 2019. The World Health Organization (WHO) has declared AMR among the top 10 global public health threats. There are certain pathogenic bacterial strains, which are also becoming multidrug-resistant, namely Mycobacterium tuberculosis (M. tuberculosis), Klebsiella pneumonia (K. pneumonia), Staphylococcus aureus (S. aureus), Streptococcus pyogenes (S. pyogenes), Pseudomonas aeruginosa (P. aeruginosa), Acinetobacter baumannii (A. baumannii), and Escherichia coli (E. coli). These strains are responsible for causing a wide spectrum of diseases in the human body.
What should be the correct course of action to tackle this situation before it becomes uncontrollable? Are there alternative therapeutic options to stop this rise in antibiotic resistance?
Self-assembled peptide gels and challenges
Scientists are investigating different ways to develop new drugs: modifying existing drugs, developing new molecules, or combining different drugs for better efficacy and treatment. Recently, gels/hydrogels have gained substantial attention due to their promising results in biomedical applications. Gel/hydrogels are semi-solid materials made from a cross-linked polymer, containing over 90% water and are biocompatible, i.e. not toxic to healthy cells. Gels derived from peptides are important due to several biomedical applications, as outlined in the image below. Peptide gels with inherent antibacterial activity can inhibit bacterial proliferation and support the growth of nearby cells.
Peptide gels are made of short or long chains of naturally occurring L-amino acids, making them suitable to be degraded by certain enzymes, including proteolytic enzymes present in our body. These enzymes recognize the amino acid or natural linkage in the amino acid structure and degrade it into simpler compounds; hence, they lose their biological function.
Recently, scientists have incorporated non-protein analogues of γ-linkage and non-natural amino acid analogues (D-amino acid) into the peptide sequence to enhance proteolytic stability, which further helps sustain antibacterial activity. The biostability of these gels was further enhanced when they were complexed with a biocompatible polymer called chitosan, known for its antibacterial activity. In other words, the complexation of the peptide with chitosan further enhances its proteolytic stability and antibacterial activity. Thus, these gels could be a promising alternative to antibiotics to prevent bacteria-related infections.
Clinical application of self-assembled peptides gels
Due to their promising potential in biomedical applications, several self-assembled peptides (SAPs) are currently in clinical trials, and others have already made their way to market. SAP hydrogel, such as RADA, is used in surgery to control bleeding and is sold under the brand names PuraMatrix® and PuraStat®. Similarly, SAP nanofiber d-EAK16 has shown potential in rabbit liver wound healing and resisting protease degradation. Other chiral SAPs are already in the market under the brand names Sciobio®-I, -II, -III, and -IV for various applications like wound healing, myocardial infarction and bone repair. Some SAP scaffolds are even in clinical trials to treat triple-negative breast cancer and tissue regeneration for dental sinus lift procedures.
A major challenge with the commercialization of SAP hydrogel is large-scale manufacturing at an affordable price. Despite several challenges, SAPs have shown promise in clinical applications and may soon become critical to curbing AMR.