In the age of antibiotic resistance, new strategies are needed to treat bacterial infections. In this scenario, bacteriophages, viruses able to infect and kill bacteria, are a potential antimicrobial alternative to antibiotics. Adsorption to the bacteria cell surface is the first step in the phage life cycle. Therefore, blocking entry points is the first line of bacteria defense and a prevalent target for phage resistance mechanisms. Now, Graham F. Hatfull, from the University of Pittsburgh, and his colleagues had just discovered how a mutation in bacteria favors resistance to phages.
Researchers focused on Mycobacterium smegmatis, a harmless relative of the bacteria responsible for tuberculosis, leprosy, and other hard-to-treat, chronic diseases. They infected the microbes with two types of engineered phages. The first one produced red fluorescence upon entering the bacteria, and the DNA of the second lit up inside the infected cell. This method made it possible to unravel for the first time how phages attach to and inject their DNA into bacteria.
But, then, Hatfull and his team made a shocking finding. If the bacterial protein Lsr2 was missing or defective, Mycobacterium smegmatis became resistant to phage infection. “Lrs2 helps bacteria to replicate their DNA. Once inside the cell, it seems that phages use Lrs2 to duplicate their own genetic material, overwhelming the microbe”, explained Roberto Díez-Martínez, CEO of Telum Therapeutics. “However, if in the absence of the protein, phages don’t replicate enough to take over the bacterial cell.
The implications of Hatfull’s work are wide. Their method could help to uncover other genes and proteins involved in phage resistance. Furthermore, knowing which are the critical steps that lead to this resistance could help to design strategies to avoid it, while taking advantage of the properties of phages. “Nonetheless, there is another alternative to phage therapy with a lower risk of resistance development: phage endolysins”, pointed Díez-Martínez. “At Telum Therapeutics we study these lytic phage enzymes, able to cleave bacteria cell wall and destroy the microbe, to use them to fight multidrug resistance bugs”.
In 2001, phage lysins were used for the first time as novel and effective antimicrobial therapy by Vincent A. Fischetti, Professor and Head of the Laboratory of Bacterial Pathogenesis and Immunology at the Rockefeller University in New York (USA), who recently joined Telum Therapeutics as chairman of its Scientific Advisory Board (SAB). Since then, 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. “We work on expanding the capacities of our APEXp® technology platform, which uses synthetic biology tools together with machine learning to design engineered endolysins and potentiate its efficacy against bacteria. We strongly believe that lysins are the future antibiotics”, concluded Díez-Martínez.
Dulberger CL, Guerrero-Bustamante CA, Owen SV, Wilson S, Wuo MG, Garlena RA, Serpa LA, Russell DA, Zhu J, Braunecker BJ, Squyres GR, Baym M, Kiessling LL, Garner EC, Rubin EJ, Hatfull GF. Mycobacterial nucleoid-associated protein Lsr2 is required for productive mycobacteriophage infection. Nat Microbiol. 2023 Feb 23. doi: 10.1038/s41564-023-01333-x.