Antibiotics have been used to combat bacterial infections for many decades now ever since penicillin was first discovered in 1928 (1). However, a major challenge we are currently facing is the increase of multi-drug resistance in bacteria. Consequently, even the most effective drugs are rendered ineffective and formerly easily treatable infections become much more difficult to cure (2).
This growing threat, in turn, has driven researchers to look beyond conventional antibiotics in the quest to find new, innovative solutions. Among the most promising therapeutic agents in this search are antimicrobial peptides (AMPs). These naturally occurring molecules may hold the key to combat multidrug-resistant pathogens and lead us through the next stages of infection control.
AMPs are naturally occurring host defense peptides that take part in the innate immune defense of animals, plants, and even humans, making them a prominent class of antimicrobial proteins. Structurally, AMPs are usually short chains of amino acids, fewer than 50, and exhibit a broad spectrum of activity, positioning them as antimicrobial peptide agents effective against various pathogens, including bacteria, fungi, and viruses. (3)
While conventional antibiotics often target bacterial cellular processes, such as protein synthesis or cell wall formation, antibacterial peptide agents like AMPs primarily attack the microbial cell wall, leading to membrane disruption and cell death. This antibacterial mechanism of action is highly effective not only against common Gram-positive and Gram-negative bacteria but also against antibiotic-resistant strains. (3) Moreover, their ability to destroy biofilm-forming bacterial communities – especially challenging to treat with conventional antibiotics – makes them a valuable prospect for future antibiotic solution. (5,6)
Antibiotic resistance has escalated into a global health crisis. The overuse and misuse of antibiotics in human medicine and animal husbandry have increased the rate at which multidrug-resistant bacteria spread. Conventional antibiotics cannot be used to kill these strains and infections caused by Methicillin-resistant Staphylococcus aureus and multi-drug-resistant Escherichia coli are increasingly occurring. Doctors are running out of effective methods to treat such infections (2,7).
Here is where peptide antimicrobial agents come into play: because they target the bacterial membrane, an integral part of bacterial structure, it is much harder for bacteria to develop resistance against them. Even in cases when mutations occur, fast and multi-targeted attacks of AMPs make them hard to adapt. This contrasts with conventional antibiotics, which often become ineffective after only a few years of widespread use as bacteria develop resistance to their active ingredients (6).
Antimicrobial peptides represent a very heterogeneous group, and their benefits extend way beyond fighting resistant bacteria. They exert effects in wound healing by reducing inflammation and the risk of infection (8), have the potential for selective action against cancer cells (9), exhibit activity against viruses like HIV and influenza (10,11), and can be used in food preservation to prolong expiration dates by reducing bacterial load. (12)
Despite such big promises, the translation of anti microbial peptides from laboratory to pharmacy shelves is still problematic. One of the major pitfalls for AMPs is the toxicity: mechanism and action targeting bacterial cells result in the unintended killing of human cells which depends on its dose and can lead to cytotoxic effects in larger quantities. Furthermore, stability problems in the human body have been reported with many AMPs. They are susceptible to enzyme degradation in the body which simultaneously diminishes their efficiency. (3)
Although AMPs are relatively short, the biological activity of most of them highly depends on their three-dimensional conformation. Considering the specific structures and folding for such peptides, the production of AMPs by chemical synthesis may be quite challenging. (3) Any structural deviations in the course of production may render these peptides ineffective. Moreover, hazardous chemicals are frequently used for large-scale peptide production, with considerable generation of chemical waste, hence rendering such methods less attractive for wider applications. (13)
The other approach is the use of recombinant technology, where microbes are genetically engineered to produce AMPs. It also has its own setbacks, as the inherent toxicity of AMPs can lead to the death of host cells, thereby giving reduced yields of the products. Besides, the process of isolation and purification of these peptides from the cells usually involves processes that are very resource-intensive and not effective due to aggregating ondr degradation-prone nature for most of the AMPs. (3,14)
To answer these challenges, Numaferm has developed the Numaswitch® platform. This new approach utilizes Switchtags, which are basically protein tags devised to allow efficient expression of AMPs in E. coli in their inactive forms to avoid toxicity. Secondly, Switchtags induce the correct refolding of the peptides in the extracellular medium, which ensures that the peptides become functionally active again. In addition to process scalability, this platform offers a cost-effective and sustainable approach for peptide (and protein) production. (15,16)
Regardless of the challenges, the prospects for AMP are encouraging. Antibiotic resistance is on the rise, and novel alternative therapeutics and methods of treatments are necessary to treat these infections. The diversity of AMPs, together with their distinctive ability to act against resistant bacteria, puts them as a potential game-changer in contemporary medicine. Several pharmaceutical companies and research organizations have already begun aggressively investing in the development of AMPs, and a few peptides have entered clinical trials already. (17)
AMPs represent a very effective, natural solution to one of the most serious contemporary problems in healthcare: resistance to antibiotics. The unique mechanism of antibacterial action in targeting and destroying bacteria makes it nearly impossible for resistance to develop, giving AMPs an edge over traditional antibiotics. Though there are still challenges ahead, the potential that AMPs hold in leading the future of antibiotic solutions cannot be disputed.
With this in mind, Numaferm engineered the Numaswitch® platform to address large-scale production problems of these therapeutic agents in a very specific way. Switchtags induce the production of AMPs in their inactive forms in E. coli and enable proper refolding in the extracellular medium in a second step. Toxicity problems of host cells are thus circumvented and contribute to the establishment of scalable and cost-efficient processes for AMP production. This represents progress that could very well be the cornerstone of infection management in a world where antibiotics are simply no longer enough.