MORE SUBJECTIVE CRITERIA (IMPACT)
Impact: Novelty/Fundamental and Broad Interest (1–4 scale) SCORE = 2
A score here should be accompanied by a statement delineating the most
interesting and/or important conceptual finding(s), as they stand right
now with the current scope of the paper. A “1” would be expected to be
understood for the importance by a layperson but would also be of top
interest (have lasting impact) on the field.
- The authors show that multiple C. sativa metabolites have
promising antibiotic potential. Furthermore, they show that CBG
specific is able to destroy biofilms and kill persister cells by
impacting the inner membrane stability of bacteria in an unknown
mechanism. Interestingly, they were unable to find a single knockout
or knockdown that all bacteria to become resistant to CBG effects.
This suggests that there may be a high genetic barrier to the
emergence of drug resistance. Finally, they were able to show that
permeabilizing/disturbing the outer membrane of Gram-negative bacteria
rendered these organisms sensitive to the effect of CBG. This is
important because we desperately need new antibiotics to target
Gram-negative bacterial pathogens.
- Due to the high likelihood of a large public interest in this work we
would like to stress the importance of a candid discussion of the
limitations of the study in the Discussion.
How big of an advance would you consider the findings to be if fully
supported but not extended? It would be appropriate to cite literature
to provide context for evaluating the advance. However, great care must
be taken to avoid exaggerating what is known comparing these findings to
the current dogma (see Box 2). Citations (figure by figure) are
essential here.
Yes, there was general agreement that this paper does provide a
significant advancement in this area of research without the
requirement of further experiments.
Impact: Extensibility (1–4 or N/A scale) SCORE = 3
Has an initial result (e.g., of a paradigm in a cell line) been extended
to be shown (or implicated) to be important in a bigger scheme (e.g., in
animals or in a human cohort)?
This criterion is only valuable as a scoring parameter if it is present,
indicated by the N/A option if it simply doesn’t apply. The extent to
which this is necessary for a result to be considered of value is
important. It should be explicitly discussed by a reviewer why it would
be required. What work (scope and expected time) and/or discussion would
improve this score, and what would this improvement add to the
conclusions of the study? Care should be taken to avoid casually
suggesting experiments of great cost (e.g., “repeat a mouse-based
experiment in humans”) and difficulty that merely confirm but do not
extend (see Bad Behaviors, Box 2).
- The authors demonstrate that their
compounds of interest could have clinical applications through the
mouse model experiment. However, the toxicity of the compounds from
both acute and chronic use was not addressed. This is a major
deficiency in the study because many compounds can kill bacterial
cells but are not considered useful antibiotics due to their toxic
effect on the host. To address this issue, we suggest that the authors
increase the duration of their animal experiments. However, we
understand that this may not be possible, in which case we would like
to see a discussion of the current literature regarding whether the
dosage of CBG in other drugs is well-tolerated and to what extent it
has been used in humans.
- We believe that the
implications from this study could be extended by using a skin
infection model in combination with polymyxin B. This would indicate
whether CBG may be a good candidate for use as a topical antibiotic
for both Gram positive and Gram-negative
bacteria.
- We believe that the
extensibility of this work could have been increased dramatically within vivo experiments that show CBG’s ability to work in multiple
different infection models. Furthermore, they could have benefited
greatly from an in vivo model showing the synergy between
polymyxin B and CBG.