From the journal RSC Chemical Biology Peer review history
A cell-permeable probe for the labelling of a bacterial glycosyltransferase and virulence factor
Round 1
Manuscript submitted on 15 июн 2023![](https://www.rsc-cdn.org/pubs-core/2022.0.146/content/NewImages/icon-letter.png)
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28-Jul-2023
Dear Dr Wagner:
Manuscript ID: CB-ART-06-2023-000092
TITLE: A cell-permeable probe for the labelling of a bacterial glycosyltransferase and virulence factor
Thank you for your submission to RSC Chemical Biology, published by the Royal Society of Chemistry. I sent your manuscript to reviewers and I have now received their reports which are copied below.
After careful evaluation of your manuscript and the reviewers’ reports, I will be pleased to consider your manuscript for publication after revisions.
Please revise your manuscript to fully address the reviewers’ comments. When you submit your revised manuscript please include a point by point response to the reviewers’ comments and highlight the changes you have made. Full details of the files you need to submit are listed at the end of this email.
Please submit your revised manuscript as soon as possible using this link :
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You should submit your revised manuscript as soon as possible; please note you will receive a series of automatic reminders. If your revisions will take a significant length of time, please contact me. If I do not hear from you, I may withdraw your manuscript from consideration and you will have to resubmit. Any resubmission will receive a new submission date.
All RSC Chemical Biology articles are published under an open access model, and the appropriate article processing charge (APC) will apply. Details of the APC and discounted rates can be found at https://www.rsc.org/journals-books-databases/about-journals/rsc-chemical-biology/#CB-charges.
RSC Chemical Biology strongly encourages authors of research articles to include an ‘Author contributions’ section in their manuscript, for publication in the final article. This should appear immediately above the ‘Conflict of interest’ and ‘Acknowledgement’ sections. I strongly recommend you use CRediT (the Contributor Roles Taxonomy, https://credit.niso.org/) for standardised contribution descriptions. All authors should have agreed to their individual contributions ahead of submission and these should accurately reflect contributions to the work. Please refer to our general author guidelines https://www.rsc.org/journals-books-databases/author-and-reviewer-hub/authors-information/responsibilities/ for more information.
The Royal Society of Chemistry requires all submitting authors to provide their ORCID iD when they submit a revised manuscript. This is quick and easy to do as part of the revised manuscript submission process. We will publish this information with the article, and you may choose to have your ORCID record updated automatically with details of the publication.
Please also encourage your co-authors to sign up for their own ORCID account and associate it with their account on our manuscript submission system. For further information see: https://www.rsc.org/journals-books-databases/journal-authors-reviewers/processes-policies/#attribution-id
Please note: to support increased transparency, RSC Chemical Biology offers authors the option of transparent peer review. If authors choose this option, the reviewers’ comments, authors’ response and editor’s decision letter for all versions of the manuscript are published alongside the article. Reviewers remain anonymous unless they choose to sign their report. We will ask you to confirm whether you would like to take up this option at the revision stages.
I look forward to receiving your revised manuscript.
Yours sincerely,
Claudia Höbartner
Associate Editor, RSC Chemical Biology
Institute of Organic Chemistry, University of Würzburg
************
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Reviewer 1
This paper report a effective probe for labelling bacterial glycosyltransferase, which can be published in reviewer’s opinion. Some additional information should be included in the revised version.
1. The protein-probe docking experiment would be beneficial for readers to understand the mechanisms of labeling.
2. The reviewer suggest the author to show NMR spectra of the intermediate products.
Minor:
Scheme 1 caption: the second (ii) should be (iii)
Fig.6 (A), (B) and (C) in the fig.6 should be (a), (b) and (c) according to the caption.
Reviewer 2
The authors present a nice study concerning the development of the first small molecule probe for the bacterial glycosyl transferase LgtC. The work is well suited to publication in RSC Chemical Biology, covering important chemical synthesis, probe developments/SAR and in vitro & whole cell evaluations. Overall, I recommend publication following minor revisions/suggestion, below.
Do the authors have any comment on which other target proteins might be labelled with their probe (similars in bacterial GT class for example?). Are there related examples of small molecule-probes for glycosyl hydrolyses? This would add some breadth to the conclusions and be of interest to the wider journal readership?
Scheme 1, R groups need to be defined in the Scheme. As is this is confusing for the reader as they have to look at Table 1 to get the coumarin identities. Relatedly the full chemical structure of 8 needs to be shown somewhere as this is unclear in its current form
The fluorescence emission paragraph should move to the ESI. Also, “stronger” emission is qualitative doesn’t add anything as no reason for the increase upon cysteine is pursued.
The Knoevenagel instability aspect. Would this really be expected at pH 7? Perhaps define the pH range that the authors consider biologically relevant.
Conclusions are before the experimental?
In the Exptal/SI:
Several 13C NMR are reported to 2dp and should be corrected to 1 dp
It would be helpful to have solvent and spectrometer frequency on the SI spectra
13C NMR of compound 8 looks to contain some impurities. Do the authors have a cleaner sample and could this have affected the results seen with compound 8?
Solids that are obtained by recrystallisation and novel should have melting points
Experimental reporting of purification by recrystallisation must add more detail (e.g., for 7a ratio of EtOAc to hexane). How easily could this synthesis be repeated without these details?
Reviewer 3
In this manuscript, Yong and colleagues elaborate a previous pyrazole-3-one covalent inhibitor for the protein LgtC, for use as an affinity-based covalent probe. Following chemical synthesis of analogues, the authors test their stability, reactivity towards nucleophiles and inhibition of LgtC in vitro, uncovering a surprisingly increased inhibitory capacity of their lead probe. The authors further investigate the compound through labeling LgtC from cell lysates and a cell preparation, to conclude that the lead probe should be amenable as a tool to detect and visualize activity in biological settings.
The manuscript is well-written, compounds are well-characterized and the conclusions are largely supported by the data. A few points require further clarification or additional proof:
- The increase in inhibitory activity through attachment of a fluorophore is impressive. However, the residual inhibition by compound 8 should be further investigated. For instance, while not a very potent Michael acceptor normally, the hydroxycoumarin moiety could still itself react with LgtC, which might also explain the increased potency of compounds 7. Thus, is compound 8 a reversible or irreversible inhibitor? Note that an in-gel experiment might give insight but might also not be sufficient because a potential reactivity of protein with the coumarin might destroy fluorescence.
- There should be a structural interpretation of the increased potency of compounds 7. Ideally, this would mean docking into a crystal/AlphaFold structure, but even displaying such a structure and highlighting a likely binding pocket would help.
- From the authors’ prior work (Ref. 3), it seems that the labeling experiment yielded a higher background in the 2-step procedure than in the new 1-step procedure. Can the authors substantiate this, comparing the two probes side-by-side, which may also further support their statements that a 1-step procedure is preferred for fluorescence.
- Being able to specifically tag LgtC in cell lystaes is important. The whole-cell assays, on the other hand, should be repeated on a living bacterial culture. It is appreciated that the authors wash cells extensively after incorporation with their probe, but it is still not ensured that these cells are indeed “intact” as mentioned in the manuscript.
- As an additional minor point, Table 1 should state that compound 8 is the reduced version since this is otherwise only stated in the text and the ESI. Only looking at Table 1, one might think that compounds 8 and 7a are the same.
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Dear Professor Höbartner,
Many thanks for sharing the reviewers’ reports on the above manuscript. I am pleased that all three reviewers take a positive view of the manuscript, and that you are prepared to consider the manuscript for publication after revisions.
Please find enclosed a point-by-point response to the reviewers’ comments as well as a revised version of the manuscript, in which all changes have been highlighted. I am confident that in the revised manuscript, we have fully addressed all the issues that have been raised.
I would like to thank you for considering this revised manuscript, and I am looking forward to hearing from you in due course.
This text has been copied from the PDF response to reviewers and does not include any figures, images or special characters:
Referee: 1
This paper report a effective probe for labelling bacterial glycosyltransferase, which can be published in reviewer’s opinion. Some additional information should be included in the revised version.
We would like to thank the reviewer for their supportive comments.
1.The protein-probe docking experiment would be beneficial for readers to understand the mechanisms of labeling. – We would like to thank the reviewer for this suggestion. We have now carried out docking experiments with 7a and the crystal structure of LgtC (PDB1GA8). These results have been included in the ESI and are being discussed in the main text.
2.The reviewer suggest the author to show NMR spectra of the intermediate products. – NMR spectra for intermediates 6a-d, 9a, 9b, 10a, and 10b have now been included.
Minor:
Scheme 1 caption: the second (ii) should be (iii)
Fig.6 (A), (B) and (C) in the fig.6 should be (a), (b) and (c) according to the caption. – We thank the reviewer for spotting these inconsistencies, which have now been corrected.
Referee: 2
The authors present a nice study concerning the development of the first small molecule probe for the bacterial glycosyl transferase LgtC. The work is well suited to publication in RSC Chemical Biology, covering important chemical synthesis, probe developments/SAR and in vitro & whole cell evaluations. Overall, I recommend publication following minor revisions/suggestion, below. – We would like to thank the reviewer for their supportive comments.
Do the authors have any comment on which other target proteins might be labelled with their probe (similars in bacterial GT class for example?). Are there related examples of small molecule-probes for glycosyl hydrolyses? This would add some breadth to the conclusions and be of interest to the wider journal readership? – We thank the reviewer for these suggestions. We had already highlighted the fact that for glycosyl hydrolases (glycosidases) – and in contrast to glycosyltransferases – a considerable number of small molecule-probes are indeed available (2nd paragraph and reference 3). As suggested by the reviewer, we have now also added a comment to the conclusion.
Regarding other target proteins labelled by the probe, preliminary data suggests that the band at 45kDa (Fig. 6) may correspond to the elongation factor Ef-Tu. We briefly discuss this in the text (p5 and Fig. 5) but feel that these results warrant full publication elsewhere.
Scheme 1, R groups need to be defined in the Scheme. As is this is confusing for the reader as they have to look at Table 1 to get the coumarin identities. Relatedly the full chemical structure of 8 needs to be shown somewhere as this is unclear in its current form – We thank the reviewer for these suggestions. We have now included the R groups in Scheme 1, and the full structures of compounds 1, 7a-d and 8 in Table 1.
The fluorescence emission paragraph should move to the ESI. Also, “stronger” emission is qualitative doesn’t add anything as no reason for the increase upon cysteine is pursued. – We agree that the observed increase in fluorescence upon addition of cysteine is purely qualitative, and we have modified the wording of this paragraph accordingly. We still believe that it is important for the reader to know that disruption of the Michael acceptor system in 7a does not adversely affect fluorescence emission. We would therefore respectfully ask to keep this short paragraph in the main text.
The Knoevenagel instability aspect. Would this really be expected at pH 7? Perhaps define the pH range that the authors consider biologically relevant. – ”Biologically relevant media” was meant to refer to the fact that these experiments were carried out in aqueous (as opposed to organic) solvent, i.e. HEPES buffer . We agree that this wording may have been misleading and have changed it.
Conclusions are before the experimental? – We followed the order of the different sections in the journal template.
In the Exptal/SI:
Several 13C NMR are reported to 2dp and should be corrected to 1 dp – We would like to thank the reviewer for pointing this out, all 13 C NMR peak lists have now been corrected to 1 decimal place.
It would be helpful to have solvent and spectrometer frequency on the SI spectra – This information has now been included on the NMR spectra.
13C NMR of compound 8 looks to contain some impurities. Do the authors have a cleaner sample and could this have affected the results seen with compound 8? – We accept that the NMR spectra of compound 8 contain some additional peaks. Most of these are solvent peaks (e.g., CD3OD at 3.21 ppm, H2O at 4.74 ppm, and ethylacetate at 1.12, 1.91 and 4.00 ppm). It is unlikely that these will have affected the results seen with compound 8, as all samples were meticulously dried before testing.
Solids that are obtained by recrystallisation and novel should have melting points – We agree with the reviewer that melting points of recrystallised compounds would have been useful. Unfortunately, we do not have this information and apologise for the omission.
Experimental reporting of purification by recrystallisation must add more detail (e.g., for 7a ratio of EtOAc to hexane). How easily could this synthesis be repeated without these details? – We thank the reviewer for pointing out this omission and have now added the ratio of EtOAc to hexane to the ESI.
Referee: 3
In this manuscript, Yong and colleagues elaborate a previous pyrazole-3-one covalent inhibitor for the protein LgtC, for use as an affinity-based covalent probe. Following chemical synthesis of analogues, the authors test their stability, reactivity towards nucleophiles and inhibition of LgtC in vitro, uncovering a surprisingly increased inhibitory capacity of their lead probe. The authors further investigate the compound through labeling LgtC from cell lysates and a cell preparation, to conclude that the lead probe should be amenable as a tool to detect and visualize activity in biological settings.
The manuscript is well-written, compounds are well-characterized and the conclusions are largely supported by the data. – We would like to thank the reviewer for their supportive comments.
A few points require further clarification or additional proof:
- The increase in inhibitory activity through attachment of a fluorophore is impressive. However, the residual inhibition by compound 8 should be further investigated. For instance, while not a very potent Michael acceptor normally, the hydroxycoumarin moiety could still itself react with LgtC, which might also explain the increased potency of compounds 7. Thus, is compound 8 a reversible or irreversible inhibitor? Note that an in-gel experiment might give insight but might also not be sufficient because a potential reactivity of protein with the coumarin might destroy fluorescence. – We would like to thank the reviewer for these suggestions. In the context of the present study, compound 8 was designed as a control compound lacking the Michael acceptor of probes 7a-d. We feel that further kinetic studies with this compound, while informative, would be beyond the scope of this manuscript. Regarding the potential reactivity of 7-hydroxycoumarin and its effect on fluorescence, we have shown that preincubation of 7a (which, like compound 8, contains a 7-hydroxycoumarin moiety) with cysteine does not destroy fluorescence. We have modified the paragraph on fluorescence emission of 7a to highlight this fact.
- There should be a structural interpretation of the increased potency of compounds 7. Ideally, this would mean docking into a crystal/AlphaFold structure, but even displaying such a structure and highlighting a likely binding pocket would help. – We would like to thank the reviewer for this suggestion. We have now carried out docking experiments with 7a and the crystal structure of LgtC (PDB1GA8). These results have been included in the ESI and are being discussed in the main text.
- From the authors’ prior work (Ref. 3), it seems that the labeling experiment yielded a higher background in the 2-step procedure than in the new 1-step procedure. Can the authors substantiate this, comparing the two probes side-by-side, which may also further support their statements that a 1-step procedure is preferred for fluorescence. – We agree with the reviewer that comparison with our previous results does suggest a higher background for the 2-step procedure than the 1-step procedure. Due to the attachment of the fluorophore, 7a is a considerably larger molecule than the corresponding probe used in the 2-step procedure. This might hinder some of the unspecific interactions with other proteins and thus reduce the background labelling of other targets in the cell lysate.
- Being able to specifically tag LgtC in cell lystaes is important. The whole-cell assays, on the other hand, should be repeated on a living bacterial culture. It is appreciated that the authors wash cells extensively after incorporation with their probe, but it is still not ensured that these cells are indeed “intact” as mentioned in the manuscript. – We would like to thank the reviewer for these suggestions. To understand the effect of 7a on a living bacterial culture, we have studied the growth of E. coli DH5α cells in the presence or absence of 7a at 25 µM and 50 µM. No significant effect on bacterial growth was observed at either concentration over a period of 6h. These results suggest that the probe does not affect bacterial viability, and that labelling does indeed occur on intact cells. These results have been included in the manuscript and are being discussed briefly (p5 and Fig. S5).
- As an additional minor point, Table 1 should state that compound 8 is the reduced version since this is otherwise only stated in the text and the ESI. Only looking at Table 1, one might think that compounds 8 and 7a are the same. – For clarity, structures of compounds 1, 7a-d and 8 have now been added to Table 1.
Round 2
Revised manuscript submitted on 30 авг 2023![](https://www.rsc-cdn.org/pubs-core/2022.0.146/content/NewImages/icon-letter.png)
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20-Sep-2023
Dear Dr Wagner:
Manuscript ID: CB-ART-06-2023-000092.R1
TITLE: A cell-permeable probe for the labelling of a bacterial glycosyltransferase and virulence factor
Thank you for submitting your revised manuscript to RSC Chemical Biology. I will be pleased to accept your manuscript for publication but would like to give you the chance to address the final comments from the reviewer(s) which are copied below.
Please revise your manuscript to address the reviewers’ comments. When you submit your revised manuscript please include a point by point response to the reviewers’ comments and highlight the changes you have made. Full details of the files you need to submit are listed at the end of this email.
Please submit your revised manuscript as soon as possible using this link :
*** PLEASE NOTE: This is a two-step process. After clicking on the link, you will be directed to a webpage to confirm. ***
https://mc.manuscriptcentral.com/rsccb?link_removed
(This link goes straight to your account, without the need to log in to the system. For your account security you should not share this link with others.)
Alternatively, you can login to your account (https://mc.manuscriptcentral.com/rsccb) where you will need your case-sensitive USER ID and password.
You should submit your revised manuscript as soon as possible; please note you will receive a series of automatic reminders. If your revisions will take a significant length of time, please contact me. If I do not hear from you, I may withdraw your manuscript from consideration and you will have to resubmit. Any resubmission will receive a new submission date.
All RSC Chemical Biology articles are published under an open access model, and the appropriate article processing charge (APC) will apply. Details of the APC and discounted rates can be found at https://www.rsc.org/journals-books-databases/about-journals/rsc-chemical-biology/#CB-charges.
RSC Chemical Biology strongly encourages authors of research articles to include an ‘Author contributions’ section in their manuscript, for publication in the final article. This should appear immediately above the ‘Conflict of interest’ and ‘Acknowledgement’ sections. I strongly recommend you use CRediT (the Contributor Roles Taxonomy, https://credit.niso.org/) for standardised contribution descriptions. All authors should have agreed to their individual contributions ahead of submission and these should accurately reflect contributions to the work. Please refer to our general author guidelines https://www.rsc.org/journals-books-databases/author-and-reviewer-hub/authors-information/responsibilities/ for more information.
The Royal Society of Chemistry requires all submitting authors to provide their ORCID iD when they submit a revised manuscript. This is quick and easy to do as part of the revised manuscript submission process. We will publish this information with the article, and you may choose to have your ORCID record updated automatically with details of the publication.
Please also encourage your co-authors to sign up for their own ORCID account and associate it with their account on our manuscript submission system. For further information see: https://www.rsc.org/journals-books-databases/journal-authors-reviewers/processes-policies/#attribution-id
Please note: to support increased transparency, RSC Chemical Biology offers authors the option of transparent peer review. If authors choose this option, the reviewers’ comments, authors’ response and editor’s decision letter for all versions of the manuscript are published alongside the article. Reviewers remain anonymous unless they choose to sign their report. We will ask you to confirm whether you would like to take up this option at the revision stages.
I look forward to receiving your revised manuscript.
Yours sincerely,
Claudia Höbartner
Associate Editor, RSC Chemical Biology
************
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Reviewer 3
The authors have addressed most of the comments. However, one issue that prevails is whether the probe actually labels protein in a living bacterial culture. The authors have shown growth curves, but they should show whether labeling similar to fig. 6 is also observed in an actively growing culture.
Reviewer 4
In this manuscript, the authors develop a small molecule probe for labelling bacterial glycosyltransferase LgtC. The authors have almost addressed the concerns of previous three reviewers. Although the author did not do whole-cell assays on a living bacterial culture, the provided related experiments can prove that the tag used does not inhibit growth. I think this manuscript is suitable for publish in RSC Chemical Biology.
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Dear Professor Höbartner,
Many thanks for considering the revised manuscript for acceptance in principle. We would also like to thank the reviewers for their additional comments. Unfortunately, we are not currently in a position to carry out the additional experiment suggested by reviewer 3, to show that labelling also occurs in actively growing culture. However, I note that reviewer 4 is satisfied that the data already included in the revised manuscript proves that the tag does not inhibit bacterial growth. We would therefore like to respectfully suggest publishing the manuscript in its current form, as recommended by reviewer 4.
I have included the required files with this submission. Please note that, as no further changes have been made to the manuscript, I have uploaded only a single version of the manuscript, without highlighting, track changes etc.
I would like to thank you and the reviewers for the critical assessment of our manuscript, which I believe has improved it considerably.
Finally, I would like to draw attention to the fact that this submission is an invited contribution to the RSC Chemical Biology themed collection: ‘Medicinal Chemistry Small Molecule Probes’ (guest editors: John Spencer, Gemma Nixon & Miraz Rahman) and as such qualifies for a waiver of all article processing charges (see email from Alexander Whiteside of 1 June 2023).
With best regards,
Gerd
Round 3
Revised manuscript submitted on 14 окт 2023![](https://www.rsc-cdn.org/pubs-core/2022.0.146/content/NewImages/icon-letter.png)
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18-Oct-2023
Dear Dr Wagner:
Manuscript ID: CB-ART-06-2023-000092.R2
TITLE: A cell-permeable probe for the labelling of a bacterial glycosyltransferase and virulence factor
Thank you for submitting your manuscript to RSC Chemical Biology. Based on all of the reviewers reports, I am pleased to accept your manuscript for publication in its current form.
You will shortly receive a separate email from us requesting you to submit a licence to publish for your article, so that we can proceed with the preparation and publication of your manuscript.
All RSC Chemical Biology articles are published under an open access model, and the appropriate article processing charge (APC) will apply. Details of the APC and discounted rates can be found at https://www.rsc.org/journals-books-databases/about-journals/rsc-chemical-biology/#CB-charges.
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