Reprogramming Bacteriophage Host Range through Structure-Guided Design of Chimeric Receptor Binding Proteins.

By M. Dunne, B. Rupf, M. Tala, Xhem Qabrati, Yang Shen, Eric. T. Sumrall, L. Heeb, A. Plückthun, M. Loessner, S. Kilcher. 2019

200 citations recorded by the source corpus.

Bacteriophages provide excellent tools for diagnostics, remediation, and targeted microbiome manipulation, yet isolating viruses with suitable host specificity remains challenging. Using Listeria phage PSA, we present a synthetic biology blueprint for host-range engineering through targeted modification of serovar-specific receptor binding proteins (RBPs). We identify Gp15 as the PSA RBP and construct a synthetic phage library featuring sequence-randomized RBPs, from which host range mutants are isolated and subsequently integrated into a synthetic, polyvalent phage with extended host range. To enable rational design of chimeric RBPs, we determine the crystal structure of the Gp15 receptor-binding carboxyl terminus at 1.7-Å resolution and employ bioinformatics to identify compatible, prophage-encoded RBPs targeting different Listeria serovars. Structure-guided design enables exchange of heterologous RBP head, neck, or shoulder domains to generate chimeric phages with predictable and extended host ranges. These strategies will facilitate the development of phage biologics based on standardized virus scaffolds with tunable host specificities.

Subfields: Biomedical Engineering, Ecology, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

Programmable protein delivery with a bacterial contractile injection system (2023, positive): “A number of studies have demonstrated that modifications to the tail fibres of phages and other bacteria-targeting CISs are sufficient to alter target specificity in predictable ways 31–34 , indicating that these proteins are important determinants of target specificity in these systems.”
Exploring Structural Diversity among Adhesion Devices Encoded by Lactococcal P335 Phages with AlphaFold2 (2022, background): “The trimeric C-terminal head domain is roughly reminiscent of the RBP head domains of lactococcal phages p2, TP901-1, Tuc2009 and Listeria phage PSA [11,27,30,50].”
A structural discovery journey of streptococcal phages adhesion devices by AlphaFold2 (2022, background): “, 2010) for phages DT1, STP1 and SW13, and with the listerial phage PSA RBP head domain for phages 9851 and TP-778L (Dunne et al., 2019) (Supplementary Table S2).”