It is well known that antibiotic-resistant microbes are becoming increasingly prevalent and that traditional antibiotics cannot cope with this growing threat. In this worrisome scenario, endolysins emerge as a solution, and we, in Telum Therapeutics, know it.
But, let’s take it one step at a time. What are endolysins?
Endolysins are proteins, and more specifically enzymes, synthesized by bacteriophages, that is, viruses that can infect and kill bacteria. Thanks to endolysins, bacteriophages cleave the peptidoglycan layer covering the bacterial cell wall during the last stage of their lytic cycle, which destroys bacteria. In a way, we see endolysins as a kind of Pac-Man, the protagonist of the popular 1980s video game that ate Pac-dots (see bacterial wall).
And how endolysins can help fight antimicrobial-resistant pathogens? Unlike current antibiotics, endolysins can target specific bacterial species, with little harm to the surrounding microbiome. Moreover, bacteria lack a resistance mechanism against these enzymes. “In order to fight antibiotic-resistant microbes, we need an agent with a radically different mechanism of action, and endolysins meet this condition”, says Dr. Roberto Díez, Chief Executive Officer of Telum Therapeutics. “Our research doesn’t focus on them by chance, but it is based on the extensive research experience on endolysins that we have accumulated over the years”.
Although phage therapy dates back to the 1920s, it was not until the 1950s that researchers realized the existence of some kind of “lytic factor” in phage lysates that was able to kill bacteria even in the absence of the virus. It has been a few years since then, but at Telum Therapeutics, we are still looking for novel phages and their endolysins. We have two main strategies for obtaining samples. On the one hand, we check unexplored caves 2,000 meters below the ground. “Well, actually cavers do it. We analyze the material they get, which is not much, but sometimes it hides very novel things”, notes Dr. Díez. On the other hand, we inspect the sewage water. “You know, where there’s dirt, there are bacteria, and where there are bacteria, there are phages.”
However, discovering new enzybiotics is not easy. Sometimes, the endolysins found are very stable but have little antimicrobial activity, and the other way around. Finding the right balance is our biggest challenge. But what about our biggest success? “It is our proprietary platform APEXp. It uses synthetic biology tools together with machine learning to design engineered endolysins composed of different activity modules of natural endolysins, in order to potentiate its efficacy against bacteria. We strongly believe that this technology is the future, as it reduces discovery time from years to months”, states the CEO.
Research data broadly support the use of endolysins as a viable therapy for multidrug-resistant bacteria. They can target both Gram-positive and Gram-negative bacteria, act synergistically with other endolysins or antibiotics, and induce the immune system. However, they also have some drawbacks. Mainly, their production cost is higher than that of antibiotics and there is no “one-size-fits-all” endolysin that can target a broad spectrum of pathogens at the same time. “Nonetheless, their efficiency, potential for engineering, and targeted mode of action give endolysins a strong advantage over conventional antimicrobials. It is, therefore, more than likely that, in the future, they will be administered independently of these”, concludes Dr. Díez.