Editorial
OPEN
A Call For a Multidisciplinary Future of Phage
Therapy to Combat Multi-drug Resistant
Bacterial Infections
Belinda Loh1, Sebastian Leptihn1,2,Y
Our trust in modern medicine is currently eroding as we come to
realize the global health crisis that is caused by pathogens that are
resistant to many, if not all, antibiotics. Soon, we will be exposed
to a situation similar to the era before the discovery of Penicillin,
where an ordinary injury, a simple cut -if infected- could result in
our lives coming to an abrupt end.1 With the emergence of
bacteria that are antibiotic resistant [antimicrobial resistance
(AMR)], governments of many countries have recognized the
criticality of this issue and have started programmes to
understand the molecular and evolutionary basis of AMR, in
order to avoid the spreading of resistance and to develop novel
treatments against multi-drug resistant pathogens.
Phage therapy – an opportunity
While it has been continuously practiced in Eastern Europe,
phage therapy currently experiences a renaissance in Western
medicine as an alternative for the treatment of bacterial infections
(Figure 1).2–7,9 In contrast to their pharmaceutical counterparts,
phages can provide versatility of being highly specific towards the
pathogen, or eliminating bacteria of certain groups. Phage
discovery has shown that phages which kill only one specific
serotype of a bacterial strain can be isolated while the opposite is
also true – phages that kill across species can be isolated as well.
Yet bacteriophages are anything but the “perfect predator.”
Evolution “designed” phages not to completely eliminate their
host, which is the optimal outcome of any medical strategy to
treat infections. However, phage-resistant strains have emerged
quickly.8
Editor: Stijn van der Veen
1
Zhejiang University-University of Edinburgh Institute (ZJU-UoE), Zhejiang
University, Haining, China., 2 Department of Infectious Diseases, Sir Run Run
Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Y
Corresponding author: Sebastian Leptihn, Zhejiang University-University of
Edinburgh Institute (ZJU-UoE), International Campus, Zhejiang University, 718
East Haizhou Rd., Haining 314400, P.R. China. E-mail: leptihn@intl.zju.edu.cn
Author contributions: Both authors BL and SL share equal contribution in
conception and writing this editorial.
Funding: No funding was received for this work.
Conflicts of interest: The author reported no conflicts of interest.
Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons
Attribution-NoDerivatives License 4.0, which allows for redistribution, commercial
and non-commercial, as long as it is passed along unchanged and in whole, with
credit to the author.
Infectious Microbes & Diseases (2020) 2:1
Received: 17 January 2020 / Accepted: 18 January 2020
http://dx.doi.org/10.1097/IM9.0000000000000018
1
Phage therapy is “personalized” medicine
Phages are highly strain specific and must be matched to the host
which is causing the disease. In this context, “personalized” does
not refer to the patient but rather to the infectious agent. Hence,
phage therapy cannot be a solution as it is currently practiced. At
the time of writing, phage therapy has only been approved in
cases that would otherwise lead to patient death. In such
instances, large phage libraries have to be rapidly screened to find
potential “cures,” phages need to be produced in large quantities
and purified, removing endotoxins and other cellular debris, to
government safety standard levels. This process of screening and
production requires time that is not available and cost-intensive.
Thus, not only fast production methods have to be developed but
also rapid screening techniques.
Past, present, and future
The years following the discovery of penicillin as the arch
compound to treat bacterial diseases in 1928, had mankind
convinced that we had already won the fight. For a long time
the opinion prevailed that no alternative strategies would be
required. Scientists would just find the “next penicillin.” Yet
antimicrobial resistance mechanisms emerged quickly with the
first resistant bacteria reported soon after the use of penicillin.9
Nonetheless, researchers developed novel compounds and it
seemed that mankind would just play a red queen game with the
bacterial world, where evolution and co-evolution would run its
course. Now, we are at a time point with a unique constellation
to our disadvantage: the industry is facing the dilemma of not
being able to produce a profitable chemical compound, as novel
drugs are kept as reserve antibiotics, and will never be sold on a
large scale, while the discovery and testing process from
compound to approval costs millions of US dollars. Thus many
programs in major pharmaceutical companies are being
discontinued10 as we seem to reach the end of the arms race,
not being able to provide more tools of war against the
microbial world.
What is required to develop phage therapy to make it a
standard medical strategy? Aside from faster screening methods
of natural phages, we should make use of the biotechnological
toolkit that is available to us to engineer genes and create new,
synthetic phages. From a biochemist’s viewpoint, viruses are
nothing more than a protein shell containing nucleic acids. One
approach could be to develop a minimal phage cassis that can
replicate well in a wide range of target bacteria. Hybrid phages
with interchangeable tails, adaptable for the target bacteria can
be created. Most phages in nature consist of a head that is almost
100% identical within the different phage types, while the tail
structures show only a low percentage of homology. For
Loh and Leptihn, Infectious Microbes & Diseases (2020) 2:1
Figure 1. Timelines of phage therapy (top) and chemical therapies (bottom) with the milestones of discoveries or therapies indicated.
selectivity, this cassis must then be combined with the receptor
binding proteins (RBPs), which have to be collected from nature,
selected by in vitro evolution in the lab, or designed using in silico
methods. The choice of RBPs will then determine the strain killed
by synthetic phage, and multivalent phages with multiple RBPs
could expand the host range, if the therapeutic phage is intended
to be used on a wider range of bacteria.
There are two ways to develop such cassis phages. One way is
to reduce the complexity of the genome of known phages,
removing “un-necessary” genes. The other way is to go from
simple to complex; the use of microviruses, ssDNA, or RNA
viruses might be advantageous because of their small size and the
fact that they are non-transducing. Whichever way we decide to
develop new phage therapy tools, it is clear that both paths stem
from the same pool of limited information.
While we try to develop ways to improve treatment
strategies, our understanding of how phages infect their hosts,
are replicated and how bacteria defend themselves, is far from
being fully understood. Developing therapeutic phages requires
our understanding of each gene (and protein) function first.
Yet, many phage genomes are not even fully sequenced, much
less the molecular function of their gene products understood.
It is high time that biologists with molecular and biochemical
knowledge stand united with microbiologists and clinicians in
the never-ending battle against pathogens. Governments have
to realize that the fundamental understanding of the processes
involved in AMR and phage-bacteria interaction are as
important, perhaps even more important, than developing
intermediate solutions. Phage therapy should not be the last
Infectious Microbes & Diseases
resort. History has provided enough evidence of its success in
the past.
References
[1] Leptihn S. Welcome back to the Pre-Penicillin Era. Why we desperately
need new strategies in the battle against bacterial pathogens. Infect
Microbes Dis 2019;1(2):33.
[2] Chanishvili N. Phage therapy—history from Twort and d’Herelle
through Soviet experience to current approaches. Adv Virus Res 2012;83
(1):3–40.
[3] Furfaro LL, Payne MS, Chang BJ. Bacteriophage therapy: clinical trials
and regulatory hurdles. Front Cell Infect Microbiol 2018;8(1):376.
[4] Hesse S, Adhya S. Phage therapy in the twenty-first century: facing the
decline of the antibiotic era; is it finally time for the age of the phage?
Annu Rev Microbiol 2019;73(1):155–174.
[5] Wright A, Hawkins CH, Anggård EE, Harper DR. A controlled clinical
trial of a therapeutic bacteriophage preparation in chronic otitis due to
antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of
efficacy. Clin Otolaryngol 2009;34(4):349–357.
[6] Schooley RT, Biswas B, Gill JJ, et al. Development and use of
personalized bacteriophage-based therapeutic cocktails to treat a patient
with a disseminated resistant Acinetobacter baumannii infection.
Antimicrob Agents Chemother 2017;61(10):e00954–e00957.
[7] O’Neill, J. (ed.). (2016). Tackling Drug-Resistant Infections Globally: Final
Report and Recommendations. The Review on Antimicrobial Resistance.
Available at: http://amr-review.org/sites/default/files/160518_Final%
20paper_with%20cover.pdf Accessed on February 25 2020.
[8] Oechslin F. Resistance development to bacteriophages occurring during
bacteriophage therapy. Viruses 2018;10(7):351.
[9] Abraham EP, Chain E. An enzyme from bacteria able to destroy
penicillin. Rev Infect Dis 1940;10(4):677–678.
[10] Lepore C, Silver L, Theuretzbacher U, Thomas J, Visi D. The small-
molecule antibiotics pipeline: 2014-2018. Nat Rev Drug Discov 2019;18
(10):739.