Phage Therapy: From Biological Mechanisms to Future Directions

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Jan 7

PMID 36608652

Authors

Steffanie A Strathdee

Graham F Hatfull

Vivek K Mutalik

Robert T Schooley

Affiliations

Soon will be listed here.

Abstract

Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to use phages therapeutically, they should (1) preferably be lytic, (2) kill the bacterial host efficiently, and (3) be fully characterized to exclude side effects. Developing therapeutic phages takes a coordinated effort of multiple stakeholders. Herein, we review the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions involving naturally occurring and genetically modified or synthetic phages.

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References

Anzalone A, Koblan L, Liu D . Genome editing with CRISPR-Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020; 38(7):824-844. DOI: 10.1038/s41587-020-0561-9. View

Goller P, Elsener T, Lorge D, Radulovic N, Bernardi V, Naumann A . Multi-species host range of staphylococcal phages isolated from wastewater. Nat Commun. 2021; 12(1):6965. PMC: 8629997. DOI: 10.1038/s41467-021-27037-6. View

Jacquemot L, Bettarel Y, Monjol J, Corre E, Halary S, Desnues C . Therapeutic Potential of a New Jumbo Phage That Infects , a Widespread Coral Pathogen. Front Microbiol. 2018; 9:2501. PMC: 6207643. DOI: 10.3389/fmicb.2018.02501. View

Mutalik V, Arkin A . A Phage Foundry Framework to Systematically Develop Viral Countermeasures to Combat Antibiotic-Resistant Bacterial Pathogens. iScience. 2022; 25(4):104121. PMC: 8983348. DOI: 10.1016/j.isci.2022.104121. View

Wright R, Friman V, Smith M, Brockhurst M . Resistance Evolution against Phage Combinations Depends on the Timing and Order of Exposure. mBio. 2019; 10(5). PMC: 6759759. DOI: 10.1128/mBio.01652-19. View

Gordillo Altamirano F, Barr J . Unlocking the next generation of phage therapy: the key is in the receptors. Curr Opin Biotechnol. 2020; 68:115-123. DOI: 10.1016/j.copbio.2020.10.002. View

Wetzel K, Guerrero-Bustamante C, Dedrick R, Ko C, Freeman K, Aull H . CRISPY-BRED and CRISPY-BRIP: efficient bacteriophage engineering. Sci Rep. 2021; 11(1):6796. PMC: 7990910. DOI: 10.1038/s41598-021-86112-6. View

Verbeken G, Pirnay J . European regulatory aspects of phage therapy: magistral phage preparations. Curr Opin Virol. 2021; 52:24-29. DOI: 10.1016/j.coviro.2021.11.005. View

Adler B, Kazakov A, Zhong C, Liu H, Kutter E, Lui L . The genetic basis of phage susceptibility, cross-resistance and host-range in . Microbiology (Reading). 2021; 167(12). PMC: 8744999. DOI: 10.1099/mic.0.001126. View

10.

Silverman A, Karim A, Jewett M . Cell-free gene expression: an expanded repertoire of applications. Nat Rev Genet. 2019; 21(3):151-170. DOI: 10.1038/s41576-019-0186-3. View

11.

Pedulla M, Ford M, Houtz J, Karthikeyan T, Wadsworth C, Lewis J . Origins of highly mosaic mycobacteriophage genomes. Cell. 2003; 113(2):171-82. DOI: 10.1016/s0092-8674(03)00233-2. View

12.

Mangalea M, Duerkop B . Fitness Trade-Offs Resulting from Bacteriophage Resistance Potentiate Synergistic Antibacterial Strategies. Infect Immun. 2020; 88(7). PMC: 7309606. DOI: 10.1128/IAI.00926-19. View

13.

Ferreira R, Sousa C, Goncalves R, Pinheiro A, Oleastro M, Wagemans J . Characterization and Genomic Analysis of a New Phage Infecting . Int J Mol Sci. 2022; 23(14). PMC: 9319048. DOI: 10.3390/ijms23147885. View

14.

Aslam S, Lampley E, Wooten D, Karris M, Benson C, Strathdee S . Lessons Learned From the First 10 Consecutive Cases of Intravenous Bacteriophage Therapy to Treat Multidrug-Resistant Bacterial Infections at a Single Center in the United States. Open Forum Infect Dis. 2020; 7(9):ofaa389. PMC: 7519779. DOI: 10.1093/ofid/ofaa389. View

15.

Kilcher S, Loessner M . Engineering Bacteriophages as Versatile Biologics. Trends Microbiol. 2018; 27(4):355-367. DOI: 10.1016/j.tim.2018.09.006. View

16.

Loponte R, Pagnini U, Iovane G, Pisanelli G . Phage Therapy in Veterinary Medicine. Antibiotics (Basel). 2021; 10(4). PMC: 8069180. DOI: 10.3390/antibiotics10040421. View

17.

Silva E, Oliveira T, Moreli F, Harada L, Vila M, Balcao V . Newly isolated lytic bacteriophages for Staphylococcus intermedius, structurally and functionally stabilized in a hydroxyethylcellulose gel containing choline geranate: Potential for transdermal permeation in veterinary phage therapy. Res Vet Sci. 2021; 135:42-58. DOI: 10.1016/j.rvsc.2020.12.013. View

18.

Thomas M, Cameron J, Davis R . Viable molecular hybrids of bacteriophage lambda and eukaryotic DNA. Proc Natl Acad Sci U S A. 1974; 71(11):4579-83. PMC: 433931. DOI: 10.1073/pnas.71.11.4579. View

19.

Sarker S, Sultana S, Reuteler G, Moine D, Descombes P, Charton F . Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh. EBioMedicine. 2016; 4:124-37. PMC: 4776075. DOI: 10.1016/j.ebiom.2015.12.023. View

20.

Hohn B, Murray K . Packaging recombinant DNA molecules into bacteriophage particles in vitro. Proc Natl Acad Sci U S A. 1977; 74(8):3259-63. PMC: 431522. DOI: 10.1073/pnas.74.8.3259. View