Enhancing phage therapy through synthetic biology and genome engineering.

Bryan R Lenneman, Jonas Fernbach, Martin J Loessner, Timothy K Lu, Samuel Kilcher

Journal: Current opinion in biotechnology 2021;68():151-159

PMID: 33310655

Free Full Text on Elsevier Science View on PubMed

Abstract

The antimicrobial and therapeutic efficacy of bacteriophages is currently limited, mostly due to rapid emergence of phage-resistance and the inability of most phage isolates to bind and infect a broad range of clinical strains. Here, we discuss how phage therapy can be improved through recent advances in genetic engineering. First, we outline how receptor-binding proteins and their relevant structural domains are engineered to redirect phage specificity and to avoid resistance. Next, we summarize how phages are reprogrammed as prokaryotic gene therapy vectors that deliver antimicrobial 'payload' proteins, such as sequence-specific nucleases, to target defined cells within complex microbiomes. Finally, we delineate big data- and novel artificial intelligence-driven approaches that may guide the design of improved synthetic phage in the future.

Address: Research Laboratory of Electronics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Synthetic Biology Center, MIT, Cambridge, MA 02139, USA.; Institute of Food, Nutrition, and Health, ETH Zürich, Schmelzbergstrasse 7, 8092 Zürich, Switzerland.; Research Laboratory of Electronics, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA; Synthetic Biology Center, MIT, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, MIT, Cambridge, MA 02139, USA; Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.; Institute of Food, Nutrition, and Health, ETH Zürich, Schmelzbergstrasse 7, 8092 Zürich, Switzerland. Electronic address: [email protected].

DOI: 10.1016/j.copbio.2020.11.003