UCSB researchers develop controlled phage therapy techniques, a potential alternative to antibiotics

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A growing concern in healthcare, antibiotic resistance weakens our ability to treat common infectious diseases.

As antibiotics become less effective, researchers are investigating possible alternative treatment methods, including phage therapy.

Bacteriophages, or phages for short, are viruses that hijack bacterial cells to reproduce. Phage therapy uses phages to fight bacterial infections. Its main attraction is its potential to work on organisms resistant to antibiotics.

However, concerns about phage therapy stem from the fact that it is a poorly controlled technique, with incomplete characterization of phage biology. The risks associated with the evolution of the phage or its exponential replication, for example, give rise to apprehensions as to its biocontrol.

Popular in the former republics of the Soviet Union, phage therapy is generally considered an option of last resort. Treatment not available in the United States, although clinical interest increases with North America first phage therapy center having opened at UC San Diego in 2019.

“Despite these problems, people have turned to phage therapy in extreme situations. Our work aims to bring phage therapy under control so that it can be used safely and more widely, ”wrote Irene Chen, associate professor in the chemistry and biochemistry department at UC Santa Barbara, in an email.

The results of the study appear in a paper published in the Proceedings of the National Academy of Sciences of the United States of America.

Chen and his team aimed to solve the problems of phage therapy by conjugating phages with gold nanorods (AuNRs), creating “phanorods”. They worked with Beth Pruitt, professor of mechanical engineering at UCSB and her lab, who provided the proof of concept on the selectivity of phage therapy to target bacterial cells without killing non-harmful cells.

“[W]We were delighted to participate in the testing of this exciting new technology for the selective killing of bacteria while preserving the health of cultured mammalian cells, ”Pruitt said via email. “This preliminary work supports the idea of ​​using such an approach in a wound healing environment to safely eradicate bacterial infections. [with] little or no toxicity to wound healing tissue.

UCSB researchers conjugated phages to gold nanorods to allow more selective targeting by killing bacterial cells without harming non-target cells. Here, the phanorods infect a cell. Courtesy of Huan Peng

Phanorods were designed to carefully target certain Gram-negative bacteria, including E. coli, P. aeruginosa and V. cholerae which infect humans, and X. campestris, which infects plants. By exciting AuNRs with near infrared light, the researchers could locally generate heat to efficiently and selectively kill bacterial cells and phages themselves, thereby suppressing any unwanted future evolution or replication of phages.

“When nanowires are exposed to certain wavelengths of light, they absorb light and convert energy into heat (the photothermal effect). This leads to very high local temperatures around the phanorods, which essentially cook the bacteria as well as the phage, while leaving non-target cells alive, ”Chen explained.

Huan Peng, a postdoctoral fellow in Chen’s lab, came up with the idea of ​​using AuNRs in phage therapy.

“Initially, we were looking for a rapid test to check the binding of certain modified phages to bacteria,” recalls Chen.

The photothermal effect of AuNRs has been used in nanomedicine techniques to treat cancer, because according to Chen, “that was the genesis of the idea of ​​using AuNRs to specifically kill bacteria. We then realized that this method would have significant advantages over other phage therapy approaches. “

To further test the potential of these phanorods, the researchers applied them to a P. aeruginosa biofilm. Biofilms are made up of a dense accumulation of bacterial cells. They present a crucial problem in the treatment of bacterial infections due to their greater resistivity to the penetration of antibiotics. Cell assembly offers an advantage because even after being subjected to antibiotics, more cells can survive than if they were individually exposed to antibiotics.

Chen et al showed extensive bacterial cell death in the biofilm as a result of phonorods. They also tested how well phanorods could kill bacterial cells without damaging surrounding mammalian cells by using them on a P. aeruginosa biofilm growing directly above canine kidney cells. Once again, scientists were able to demonstrate widespread bacterial cell death as well as the survival of the majority of kidney cells (84%).

“Showing that biofilms can be destroyed by phanorods suggests that phanorods might work in physical scenarios when antibiotics couldn’t,” Chen said.

The next major step is to study phage therapy in more realistic models of bacterial infections, according to Chen. “In addition, it is important for us to increase the number of germs that we can target. “

“At present, there are many reasonable hesitations about phage therapy due to the lack of control over these biological entities. We believe that controlling phage therapy in this way could allow phages to become an acceptable therapy for use in antibiotic resistant infections, ”Chen said.

Jacqueline Wen

Jacqueline is the science and technology writer. She enjoys watching movies and learning about science and technology.


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