A Blueprint for Broadly Effective Bacteriophage Therapy Against Bacterial Infections

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Bacteriophage therapy is a tantalizing therapeutic option for anti-microbial resistant bacterial infections but is currently limited to personalized therapy due to the narrow host range of individual phages. Theoretically, cocktails incorporating numerous phages targeting all possible bacterial receptor specificities could confer broad host range. Practically, however, extensive bacterial diversity and the complexity of phage-phage interactions precludes this approach. Here, using screening protocols for identifying “complementarity groups” of phages using non-redundant receptors, we generate effective, broad-range phage cocktails that prevent emergence of bacterial resistance. Further, phage complementarity groups have characteristic interactions with particular antibiotic classes, making it possible to predict phage-antibiotic as well as phage-phage interactions. Using this strategy, we generate three phage-antibiotic cocktails, each effective against >96% of 153 Pseudomonas aeruginosa clinical isolates, including when used in biofilm cultures and wound infections in vivo . We similarly develop effective Staphylococcus aureus phage-antibiotic cocktails and demonstrate the utility of combined cocktails against polymicrobial (mixed P. aeruginosa/S. aureus ) cultures, highlighting the broad applicability of this approach. These studies establish a blueprint for effective, broad-spectrum phage therapy cocktails and enable off-the-shelf phage-based therapeutics for antimicrobial-resistant bacterial infections.

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  1. Next, we investigated whether our strategy is also applicable in an animal model of wound infection

    Really impressive that you also did the mouse work to see if this held up in vivo!

  2. We obtained comparable results regardless of the MOI used, despite the sub-maximal initial inhibition effects at lower MOIs (Fig. 1A-iii).

    While this may be true for DMS3, it may not be universally true for some of the other phages you are using in this panel. For instance, phiKZ can only infect PA14 at high MOIs due to the activity of a jumbophage targetting immune system. Infection with KZ would certainly fail at some of these lower MOIs.

    Check out this preprint for more info: https://www.biorxiv.org/content/10.1101/2022.09.17.508391v1.full

  3. While beyond the scope of this work, understanding the mechanisms underlying these patterns will be important for the future success of this approach

    Totally agree! i found this to be a really interesting part of your work.

  4. We observed that phages belonging to the same complementary group generally share common patterns of interactions with conventional antibiotics

    To me looking at these data, it appears that the patterns of synergy are being driven by the antibiotic more so than the phage receptor group for both S. aureus and PA14. I think theres some interesting stuff there with phage x antibiotic relationships (like why is Rif so antagonistic in S. aureus?) but I'm not convinced most of the signal is coming from the receptor group. I do think that there could be some cases where it would be - like when the receptor is an antibiotic efflux pump - but thats not the case for most of these phages.

    If you want to pursue the receptor x antibiotic angle, it could be interesting to test the susceptibility of the receptor KO strains to antibiotics. That might give you more direct information about how the phage receptor and the antibiotic may be influencing each other.

  5. This Zenodo record is a permanently preserved version of a Structured PREreview. You can view the complete PREreview at https://prereview.org/reviews/11474323.

    Does the introduction explain the objective of the research presented in the preprint? Yes
    Are the methods well-suited for this research? Highly appropriate
    Are the conclusions supported by the data? Highly supported
    Are the data presentations, including visualizations, well-suited to represent the data? Highly appropriate and clear
    How clearly do the authors discuss, explain, and interpret their findings and potential next steps for the research? Very clearly
    Is the preprint likely to advance academic knowledge? Highly likely I was interested in reading this work because it overlaps with my own (unpublished) work. I'm excited to see someone so clearly articulate things that I have had success with in my own experience working on phage complementarity for robust phage cocktails. I imagine this will be a very useful foundational reference for myself and others in the field going forward that highlights the theory and practice of executing these designs effectively.
    Would it benefit from language editing? No
    Would you recommend this preprint to others? Yes, but it needs to be improved Having figures and legends separate makes the efficiency of reading lower than it would otherwise be in final (or near final) print format, but the formatting does not detract from the quality. I am aware that this is the preferred submission format for many journals so it should not prevent others from engaging with it at this stage, if they would prefer to engage with it now rather than waiting for peer-reviewed publication.
    Is it ready for attention from an editor, publisher or broader audience? Yes, as it is

    Competing interests

    I have met and discussed phage cocktail designs with the senior author, but I do not know the lead author or any of the co-authors. I was not involved with or aware of this particular work prior to publication, and did not receive any funding, authorship, or other forms of financial or professional compensation that I believe would bias my subjectivity.