Translating phage therapy into the clinic: Recent accomplishments but continuing challenges

Abstract

Phage therapy is a medical form of biological control of bacterial infections, one that uses naturally occurring viruses, called bacteriophages or phages, as antibacterial agents. Pioneered over 100 years ago, phage therapy nonetheless is currently experiencing a resurgence in interest, with growing numbers of clinical case studies being published. This renewed enthusiasm is due in large part to phage therapy holding promise for providing safe and effective cures for bacterial infections that traditional antibiotics acting alone have been unable to clear. This Essay introduces basic phage biology, provides an outline of the long history of phage therapy, highlights some advantages of using phages as antibacterial agents, and provides an overview of recent phage therapy clinical successes. Although phage therapy has clear clinical potential, it faces biological, regulatory, and economic challenges to its further implementation and more mainstream acceptance.

Fig 1. Phage lytic infection cycle.

The phage infection cycle. This flows counterclockwise in the figure, starting from the upper left. (1) Phage attachment to receptor molecules found on bacteria [29,30] is typically described as processes of virion adsorption [31,32] with uptake involving movement of the virion genome from the phage virion into the bacterial cytoplasm. This can lead to the noted lysogenic cycles (main text) or, in some cases instead, pseudolysogeny [–35], but as shown, particularly for virulent phages, gives rise to lytic cycles. (2) Synthesis is of phage-specific macromolecules including RNA, DNA, and proteins. Assembly is the process of generation of new virions from those macromolecules as resulting, ultimately, in (3) maturation of virions into adsorption proficient entities. (4) The timing of liberation of virions generally is under phage genetic control [36], though for certain types of phages (not tailed and also not shown), this release occurs chronically rather than lytically [25].

Fig 2. Milestones in phage science and phage therapy.

Milestones in phage science and phage therapy. Abbreviations include GMP, good manufacturing practice; IV, intravenous; JAMA, Journal of the American Medical Association. Early general references include [–68] and [1,69]. Additional references used to create the figure include from 1963 [70], 1987 [71], 2001 [72], 2008 [73], 2009 [74], 2012 [75], and 2021 [76]. Icon copyright attributions by first-use year (all as obtained via thenounproject.com and presented parenthetically; superscripts are associated country abbreviations): 1896 (Studio 365 ^TH), 1889 (pongsakorn ^TH), 1912 (Luiz Carvalho ^BR), 1919 (Sergey Demushkin ^RU), 1920 (Arafat Uddin ^BD), 1923 (Wuppdidu ^DE), 1929 (Irfan Setiawan ^ID), 1931 (Adrien Coquet ^FR), 1930s (Mourad Mokrane ^RU), 1939 (Soremba ^DE), 1940 (Cassandra Cappello ^CA), 1942 (Icon Lauk ^ID), 1940s (WEBTECHOPS LLP ^IN), 1963 (Adrien Coquet ^FR), 1976 (Eko Purnomo ^ID), 1982 (One Pleasure ^ID), 2001 (Kelsey Armstrong ^US), 2006 (Nendra Wahyu Kuncoro ^ID), 2008 (Creative Stall), 2009 (Kamin Ginkaew ^TH), 2018 (Kamin Ginkaew ^TH), 2019 (Wikimedia Commons), 2019 (Irfan Setiawan ^ID), 2020 (Wikimedia Commons), 2021 (Irfan Setiawan ^ID).

Fig 3. Recent clinical phage therapy accomplishments.

Targets of recent phage therapy trials and case studies include Achromobacter xylosoxidans, Acinetobacter baumannii, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Mycobacterium abscessus, Mycobacteroides chelonae, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus mitis. Abbreviations include GMP, good manufacturing practice; MDR, multidrug resistant; MRSA, methicillin-resistant S. aureus. References used to create the figure: [,,–124]. See also [78] for a more complete list of modern phage therapy clinical studies showing evidence of phage-mediated efficacy. Icon attributions can be found in the legend to Fig 2, corresponding respectively to years 1915 and 2019 (in combination), 2009, and 2018.

Fig 4. Challenges to more widespread adoption of phage therapy.

At the top are issues that are more biological in their character, whereas at the bottom are issues that are more societally imposed impediments to greater phage therapy implementation. Not shown but associated with the latter are difficulties that physicians can face in simply obtaining treatment phages in countries where phage therapy is not already a standard of care.