Bacteriophage enzymes: a new realm of antibiotics
Written By: Reed Owens-Kurtz
Edited By: Claudia Althoen, Madeline Nicol, Katherine Hill
Microbes have been sources for antibiotics since the heralded discovery of Penicillin. However, the applications of viruses in our fight against pathogenic microbes has long been neglected. The ability of bacteriophages, viruses that target bacteria, to selectively target pathogens has just recently been explored, opening an entire realm of potential antimicrobials. Unlike conventional antibiotics, these bacteriophage-derived treatments may be able to specifically target and affect only harmful pathogens, reducing negative effects on the healthy microbiome. They also have the potential to enter human cells and kill pathogens hiding within. These newly discovered bacterial assassins produced by bacteriophages are single proteins called endolysins.
Endolysins are enzymes that kill bacteria by bursting their cell walls. Bacteriophages make specific endolysins that destroy the bonds in peptidoglycan, the primary material in bacterial cell walls. Shen et al. studied an endolysin that kills Streptococcus pyogenes,abbreviated Spy, the pathogen behind strep throat, necrotizing fasciitis, and streptococcal toxic shock syndrome. They analyzed how this anti-strep endolysin, called PlyC, functions and whether it could target harmful bacteria that hide inside human cells in the throat, avoiding conventional antibiotics. Their work showed that PlyC could enter human cells infected with Streptococcus and identify and lyse only these pathogens. This implicates a unique potency of endolysins in the treatment of pathogens that can intracellularly evade traditional antibiotics and the human immune system.
A team of researchers headed by Yang Shen at the University of Maryland, Carnegie Mellon University, and the Rockefeller University developed a culture of human epithelial cells and Spy to mimic an infection. They originally aimed to develop engineered endolysins to target Spy cells hiding inside the human cells, and as a control, measured the efficacy of a few known endolysins against intracellular Spy to establish the levels of Spy in the cells when treated with these purified but unmodified endolysins. Much to the scientists’ surprise, the endolysin PlyC killed 95% of the intracellular bacteria without the need for engineering. After this shockingly eventful control test, the researchers focused on PlyC’s activity, determining whether it has any adverse consequences on the human cells and the role of its different domains. Using confocal microscopy to visualize stained cell membranes, they demonstrated that the human epithelial cells were unaffected by PlyC. Fluorescent staining of Spy and of the endolysin showed that they aggregate in the same regions of the human cell. Therefore, PlyC is likely associated with Spy within human cells, providing reasonable evidence that it targets only the pathogen. Further experiments investigated the subunits of PlyC and found that the subunit PlyCB was essential for the enzyme to enter the human cell. This series of microscopy demonstrates that the endolysin requires these subunits to enter human epithelial cells and zones in on Streptococcus pathogens once in the cell.
Will the next antibiotic your doctor prescribes be a bacteriophage-produced enzyme? Shen et al. are continuing their research on PlyC with goals to determine the molecular mechanisms behind how this enzyme kills Spy. They hope to fully understand this endolysin, including any potential side-effects on human cells, before proposing it as a new drug. This recent paper certainly shows potential for PlyC as an antibiotic that succeeds where current drugs fail in treating intracellular infections. It also exposes a whole category of untapped biological sources for antibiotics. After all, recent estimates suggest the world contains 1031 bacteriophages — why not harness this vast array of organisms evolved to kill bacteria with precision? Take your pick, there’s a bacteriophage assassin for any bacteria you want to get rid of, and these first experiments suggest they are much better at finding and killing pathogens than we are.
Citations:
Shen, Y. et al. A bacteriophage endolysin that eliminates intracellular streptococci. eLife 5, e13152 (2016).
Travis, J. All the World’s a Phage. Science News, 164(2), 26 (2003).
Loessner MJ. Bacteriophage endolysins–current state of research and applications. Current Opinion in Microbiology 8, 480–487 (2005).
