Stephen T. Abedon

Department of Microbiology – The Ohio State University

phage.org – phage-therapy.org – biologyaspoetry.org

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We’re all biased by what we know best and the link below discusses why, historically as well as microbiologically, we all “grew up” with the notion that envelope mutations are the primary means by which phage resistance evolves in bacteria. So thank you E. coli (I state with sarcasm):

http://schaechter.asmblog.org/schaechter/2014/11/why-crispr-doesnt-work-in-.html

What, I ask, are the implications for phage therapy of resistance mechanisms to specific phages that are essentially cost free and, at least arguably, Lamarckian as well, i.e., as due to CRISPR? For well-trained phage-therapy teams, I suspect not much. This is because, whether employing cocktails or monophages, the intention generally will be to hit bacterial targets hard and with whatever it takes to clear the infection, such as to switching phages during monophage therapy if resistance is noted.

But for monophages in the hands of less well-trained individuals, e.g., over-the-counter phage formulations or in the hands of poorly trained or regulated clinicians, the potential for development and then transmission of fully fit pathogens that nonetheless are fully resistant to a specific monophage could be fairly high. Importantly, and as relevant to the cited E. coi-CRISPR story, this issue may be more relevant for some pathogens, i.e., those with intact CRISPR systems, than it is for others.

So perhaps we can add inhibition of the potential for therapy-induced evolution of phage resistance among pathogens – as could then be transmitted across affected human communities – as an additional advantage of  prêt-à-porter (phage cocktails) versus sur-mesure (monophage therapy), while still retaining an argument for sur-mesure particularly among highly experienced phage therapists.

As we note in Chan and Abedon (2012), I nevertheless don’t buy arguments that spontaneously occurring phage host range mutations can be counted on in situ to counter bacterial evolution to phage resistance whether in the context of phage cocktails or instead monotherapy. From p. 19 of that publication:

A further consideration is that just as cocktails of phages may be thwarted in their ability to target low densities of phage-resistant bacteria, particularly given active treatment, these concerns should be even greater if one is relying on in situ phage evolution to supply resistance-countering phages… The reason for this is that the necessary host-range mutant phage types will be present in even lower densities than the phages explicitly found in cocktails. These same concerns may also be seen even in the absence of spatial structure so long as those phages within a cocktail that are amplified in situ, that is, in the course of active treatment, are not the same phages to which bacterial phage-resistant mutants are sensitive… Active therapy even with phage cocktails thus may be inherently incompatible with early interference with the evolution of bacterial resistance to phages.

 

Phage cocktails nevertheless should be better suited than monophages for dealing with evolving bacterial resistance to phages simply because cocktails inherently possess greater total numbers of phage particles that display divergent host ranges. On the other hand, the generation of cocktails of phages that display divergent host ranges – but where those phages nevertheless have been derived from a common genetic “platform” – might be expected to perform little better than monophages in the face of CRISPR-mediated phage resistance in target bacteria.

Further (Phage Therapy) Reading:

Chan, B. K., S. T. Abedon, and C. Loc-Carrillo. 2013. Phage cocktails and the future of phage therapy. Future.Microbiol. 8:769-783. [PubMed]

Chan, B. K. and S. T. Abedon. 2012. Phage therapy pharmacology: phage cocktails. Adv.Appl.Microbiol.  78:1-23. [PubMed]

Pirnay, J. P., V. D. De, G. Verbeken, M. Merabishvili, N. Chanishvili, M. Vaneechoutte, M. Zizi, G. Laire, R. Lavigne, I. Huys, G. Van den Mooter, A. Buckling, L. Debarbieux, F. Pouillot, J. Azeredo, E. Kutter, A. Dublanchet, A. Gorski, and R. Adamia. 2011. The phage therapy paradigm: prêt-à-porter or sur-mesure? Pharm.Res 28:934-937. [PubMed]