Phage therapy: Should bacterial resistance to phages be a concern, even in the long run?

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by  Ormala, Anni-Maria

Views and CoMMentaries Views and CoMMentaries
Bacteriophage 3:1, e24219; January/February/March 2013; © 2013 Landes Bioscience
Phage therapy
Should bacterial resistance to phages be a concern, even in the long run?
Anni-Maria Örmälä1 and Matti Jalasvuori2,3,*
1Department of Biosciences; University of Helsinki; Helsinki, Finland; 2Center of Excellence in Biological Interactions; Department of Biological
and Environmental Science; University of Jyväskylä; Jyväskylä, Finland; 3Division of Ecology, Evolution and Genetics; Research School of Biology;
Australian National University; Canberra, Australia
Bacteriophage therapy, the use of viruses such as conjugative plasmids,2 and a single
that infect bacteria as antimicrobials, has element can confer resistance to many dif-
been championed as a promising alterna- ferent antibiotics.3 Furthermore, plasmids
tive to conventional antibiotics. Although spread and persist within populations
in the laboratory bacterial resistance even in absence of antibiotics, suggesting
against phages arises rapidly, resistance so that decrease in the use of antibiotics is
far has been an only minor problem for the not likely to help the situation.4 Although
effectiveness of phage therapy. Resistance there may be means to get rid of the resis-
to antibiotics, however, has become a tance or prevent its spread,3 more gener-
major issue after decades of extensive use. ally effective alternatives to conventional
Should we expect similar problems after antibiotics would be useful for combatting
long-term use of phages as antimicrobials? those bacterial pathogens that present as
Like antibiotics, phages are often noted to antibiotic resistant.
be drivers of bacterial evolution. Should we The ability of bacteriophages to
expect phage-treated pathogens to develop clear and kill bacteria often inspires the
a general resistance to phages over time, a idea that these bacterial viruses may be
resistance against which only, for example, included among these possible alternatives
hypothetically co-evolved phages might to conventional antibiotic agents, that is,
be infective? Here we argue that the global as selectively toxic antibacterials. This ini-
infection patterns of phages suggest that tial excitement, however, can fade when
this is not necessarily a concern as envi- it transpires that bacteria also can rapidly
ronmental phages often can infect bacteria develop resistance to phages, even within
with which those phages lack any recent relatively small bacterial populations (of,
co-evolutionary history. e.g., about 108 cells).5 Bacteria can become
Bacterial pathogens have been treated resistant by several mechanisms, includ-
effectively with antibiotics for several ing for example alteration of receptors to
Keywords: evolution, ecology,
decades. However, the extensive use of which phages attach or the development
phage-therapy, antibiotic resistance,
antibiotics, both properly and improperly, of adaptive immunity via interfering
phage resistance
has generated strong selection pressure for CRISPR sequences.6 Although mecha-
Submitted: 06/29/12 bacteria to become resistant.1 Antibiotic nisms of bacterial resistance to phages dif-
resistant strains are becoming increas- fer substantially from those of chemical
Revised: 03/06/13
ingly more common and thus infections antibiotics, the overall result from the per-
Accepted: 03/06/13 acquired especially within hospital set- spective of therapy is the same: bacterial
Citation: Örmälä A.-M. , Jalasvuori M. ; Phage tings often are untreatable with conven- proliferation can no longer be controlled
therapy: Should bacterial resistance to phages be tional therapies. Bacteria typically need by therapeutic agents. Noting the rap-
a concern, even in the long run? Bacteriophage only few genes to become resistant to com- idly emerging resistance, the advocates of
2013; 3:e24219; http://dx.doi.org/10.4161/bact.24219
monly used antibiotics. These resistance- phage therapy usually bring up the benefits
genes often move horizontally between of phage cocktails, in which many differ-
*Correspondence to: Matti Jalasvuori;
Email: [email protected] bacteria within selfish genetic elements, ent types of phages infect the same species
www.landesbioscience.com Bacteriophage e24219-1
or strains, and thus make the emergence of molecular evolution of the coevolving trait of the bacterium. Similarly, viruses
of a resistant bacterial cell substantially species even in laboratory conditions.11,18,19 were less infective to current bacteria than
less likely.7,8 Yet, there remains a lingering Although not all viruses seem to be able future or past hosts, suggesting that virus
concern that extensive use of phages will to adapt to infect resistant hosts16,20 this predation was not able to induce changes
select in one way or another for bacterial scenario nonetheless gives the impres- that would allow only the coevolved
strains that are resistant to phage-cock- sion that at least some phages can remain viruses to remain infective to their hosts.
tails. As Krylov et al. has recently argued, infective only by constantly evolving in This, in turn, suggests that viral selec-
it might be more reasonable to use only a terms of their host range.16 If pre-defined tion is not forcing genetic divergence that
single lytic phage, one very specific to the phage cocktails were used globally and would also prevent the replication of other
pathogen causing an infection, in order to continuously in a manner similar to that viruses in any particular host. Phage resis-
prevent the emergence of bacteria that are of antibiotics, resulting in bacterial evolu- tance in many cases can be costly for the
resistant to the valuable broad-host range tion but not antimicrobial evolution, then bacterium22,23 and it thus appears to be
cocktails.9 Perhaps equivalently to chemi- it is possible that phages could with time disadvantageous for the bacteria to remain
cal antibiotics, after decades of use of become ‘over-evolved’ by their hosts. resistant against bacteriophages that are
phages numerous bacterial pathogens may Evolution of bacterial resistance to no longer present in their local environ-
be resistant to various phage-cocktails, phages, may occur more slowly given ment.21 Moreover, phage-resistant bacteria
resulting in major difficulties in treat- use of phage cocktails rather than indi- often lack important surface features that
ing, e.g., hospital acquired (nosocomial) vidual phages, but nevertheless only delay are responsible for bacterial virulence.24,25
infections.10 the evolution of bacterial superbugs that Resistant bacteria, even if they are not
Phages are often stated to drive bac- are highly resistant, generally, to phages. killed by phages, therefore can become
terial evolution,11 with phages forcing Alternatively, to the extent that broad mostly harmless. However, sometimes
adaptations within bacterial populations, bacterial resistance to phages can evolve, there has been no observable costs associ-
especially phage resistance. Generally cocktails by supplying multiple phages ated with resistance,20,26,27 demonstrating
phages have a narrow host range and this simultaneously could select precisely for that resistant phenotypes, at least under
is so to such an extent that the specificity such hypothetically broadly phage-resis- certain conditions, may persist.
of a set of different phages has been rou- tant bacteria. In any case, this concern, Even if continuous use of phages
tinely used to distinguish closely related no matter how hypothetical, we feel is forced a bacterial population to become
bacterial strains from one another.12 a reasonable interpretation of the more permanently resistant to specific phage-
Given the narrow host range, the con- general concern that phage therapy may cocktails, biogeography studies of phage
tinuous selection for resistance and the suffer the same fate of antibiotic therapy: infection patterns suggest that new infec-
often mentioned evolutionary arms race the evolution of superbugs for which it tious phages will nevertheless be avail-
between bacteria and phages,13,14 might is difficult to identify new antibacterials able. It has been shown that regardless
we suspect difficulties in future attempts against which resistance is not already of the absence of recent contact, phages
to isolate phages that are effective against present. Alternatively, it could be argued have remained infective to bacterial host
potentially multi-phage-resistant bacte- that perhaps only co-evolved phages that cells on the other side of the world. This
rial strains and may this compromise the have responded evolutionarily in course of is despite the fact that most bacteria are
long-term viability of phage therapy? It ongoing bacterial evolution to phage resis- thought to be under constant evolutionary
is specifically this latter question that we tance may remain infective against these arms race with the phages in their pres-
address in this commentary. hospital specific strains, that is, phages ent environment.11 For example, meta-
Phage impact on bacterial evolution responding mutation by mutation rather analysis of host-phage interactions of 38
can occur in the course of antagonistic than simultaneously to large numbers separate studies performed by Flores et
co-evolutionary cycles.15,16 In these cycles, of anti-phage resistance alleles that have al. concluded that phages can often infect
viruses evolve to re-infect hosts that have accumulated in target bacteria. many different host strains from different
already become resistant to earlier types Despite of the above mentioned obser- origins.28 They pointed out that infection
of the same virus.13,14 It has been shown vations on bacterial evolution, several patterns were nested, indicating that the
moreover that the frequency of bacterial studies are suggestive that evolution of ‘hard to infect’ hosts were infected by gen-
reversion back to phage-susceptible phe- phage-resistant superbugs is not going to eralist phages and not by selective special-
notypes is relatively low.17 Surface compo- occur. First, the cycles of viral adapta- ists. Correspondingly, Wolf et al. showed
nents of bacterial cells in particular evolve tion to evolved hosts and vice versa have in 2003 that they were able to isolate bacte-
rapidly, which likely is due to the fact been experimentally shown in laboratory riophages from distant geographical loca-
that they are utilized by phages for host conditions and natural habitats. Gomez tions for a single freshwater bacterial host
attachment (though also, for pathogens, and Buckling (2011) in particular demon- (Sphingomonas sp) isolated in 1985.29 One
could be a consequence of immune sys- strated that bacteria in soil were more resis- of us recently isolated phages from Finland
tem evasion). Co-evolutionary arms races tant to their contemporary phages than to for bacterial strains that were originally
between bacteria and their lytic viruses past or future phages.21 Host resistance to collected from Britain in the sixties. These
also have been shown to accelerate the rate phage infection was thus only a temporary and other examples have demonstrated
e24219-2 Bacteriophage Volume 3 issue 1
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