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PONE-D-22-18915In-vivo studies on Transitmycin, a potent Mycobacterium tuberculosis inhibitorPLOS ONE

Dear Dr. Dusthackeer,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by October 17, 2022. If you will need significantly more time to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

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2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. 

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript: 

"Authors thanks the Indian Council of Medical Research for providing 

 grant-in-aid (F.No.5/8/5/8/TF/2017/ECD-I) to conduct this preclinical study on Transitmycin".

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. 

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: 

"The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript".

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. We note that you have included the phrase “data not shown” in your manuscript. Unfortunately, this does not meet our data sharing requirements. PLOS does not permit references to inaccessible data. We require that authors provide all relevant data within the paper, Supporting Information files, or in an acceptable, public repository. Please add a citation to support this phrase or upload the data that corresponds with these findings to a stable repository (such as Figshare or Dryad) and provide and URLs, DOIs, or accession numbers that may be used to access these data. Or, if the data are not a core part of the research being presented in your study, we ask that you remove the phrase that refers to these data.

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6. Please include a copy of Tables 1 and 6 which you refer to in your text on pages 7 and 19, respectively.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: In general, this manuscript is badly prepared, the authors need to take the submission of their work seriously. There are lots of issues the authors need to seriously address, below are some but not all:

1. Line 231, please keep the citation format consistent.

2. Line 272, what is exact range of <0.312 and 40, 0 is also <0.312, this way of expression is very unprofessional.

3. Line 273, A maximum of 19 and 15 isolates got inhibited at a 5μg ml-1and 10μg ml-1concentration of TR respectively. Why a lower concentration has a higher number of inhibited isolated?

4. The authors did not properly assign and arrange figures and supplementary figures, I see a number of supplementary figures while only a few figures in main text.

5. The authors did a terrible job in preparing figures. In figure1, what are the numbers under the X axis? What is the Y axis? What are the units? two drug susceptible isolates of M. tuberculosis, which one is the first one, which is the second? I have a difficulty in understanding this figure 1, the authors definitely need to explain more detail in the figure legend.

6. From the figure 1, if my interpretation is correct, this TR chemical is not even as efficient as kanamycin, what's the significance of the usage of this chemical to treat TB?

7. Figure 2 has no units and detailed figure legend.

8. Figure 3, at least the authors should keep the style, format, such as font and size consistent. In addition to this issue, no legend. What are G1 G2 and G3, why G2 and G3 stopped after week5 or 6?

9. Line 332, the authors need to write the numbers in a more scientific format, what is the number of ~6.10 log10? The authors need to go through the entire text and figures and tables to list numbers in a scientific way.

10. Line 351, what is PK?

11. Line 357, a docking analysis is not able to confirm anything, it is a simple prediction.

12. Line 369. Hence it could be concluded that the anti-mycobacterial activity of TR is because of its DNA intercalation property. I do not see sufficient data to conclude this, docking prediction analysis does not count.

13. Line 380, the analogs interaction with DNA needs to be experimentally tested but not just by prediction.

14. Line 421, how do the authors know RecA is a target of TR, again the prediction analysis does not serve as an evidence.

15. Missing reference for suramin.

16. Line 433, the authors do not have experimental data suggesting TR hits the above 3 targets.

17. Line 590, what is supplementary figure1, please do not simply crop the image from somewhere else without even erasing extra contents. And again, the authors should learn how to write a proper figure legend to explain figure contents.

18. Supplementary figure 4, 5 and 10 are redundant to main figures.

19. Supplementary figure 6, what are a b,c? Simply stacking figures while not explaining them will not serve well to explain your study.

20. Supplementary figure 14, what are the organs?

Reviewer #2: 1. Please provide the source of all the chemicals and biologicals (bacteria, animals)

2. L98 I am not sure if the ratio is written correctly ( 100%:1%)

3. there are two sets of supplementary figures and tables with this manuscript. One at the end of it and another as a supplementary file. This created a lot of confusion for me. Please combine them into one and number them correctly. A lot of supp figures and table were not referenced in the manuscript.

4. Please provide a figure with TR and all its analogues in the manuscript

5. L127. Provide reference for broth microdilution method here

6. Please provide a brief description of the LRP assay

7. Need more description about the Pharmacokinetic study on TR method

8. L164, Possible typo, the peritoneal route?

9. L169, typo, titered.

10. L198, should be supp fig 2.

11. L205, please refer to supp fig 3. Fig needs to be reformatted.

12. L246, which software was used? How the analysis was done. Need more information for the methods.

13. L249, how the fluorescence was collected? Plate reader/ fluorimeter etc?

14. Fig 1 and 2 needs more information in the legend. In its current form I can not understand what any of these figure means. What is in X and Y axes? Probably need more detail method about the experiment.

15. Paragraph 287, Please summarize the result in a table or figure

16. Figure 3 needs more information in the legend. What are those lines? What is G1, G2 G3?

17. L306, 308. Again wrong figure was referenced here

18. L308, I think there is a figure missing here for histopathological examination.

19. L313 wrong fig referenced. Some the bar graphs have no error bars

20. L338 wrong figure cited

21. L347, 348 only headings?

22. L355, what kind of basic analysis showed this?

23. L363 wrong figure

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-22-18915R1In-vivo studies on Transitmycin, a potent Mycobacterium tuberculosis inhibitorPLOS ONE

Dear Dr. Dusthackeer,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

In accordance with PLOS ONE’s submission guidelines pertaining to humane endpoints (http://journals.plos.org/plosone/s/submission-guidelines#loc-humane-endpoints), please provide further details the humane end points experimental procedures. In particular please provide more clarity on the 6 experimental groups used, a survival curve for this study, the rationale for performing the infection/efficacy study reported in Figure S2, and specify if any animals died before meeting the criteria for euthanasia. 

Please submit your revised manuscript by Jan 30 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Fred Quinn

Academic Editor

PLOS ONE

Additional Editor Comments:

In accordance with PLOS ONE’s submission guidelines pertaining to humane endpoints (http://journals.plos.org/plosone/s/submission-guidelines#loc-humane-endpoints), please provide further details the humane end points experimental procedures. In particular please provide more clarity on the 6 experimental groups used, a survival curve for this study, the rationale for performing the infection/efficacy study reported in Figure S2, and specify if any animals died before meeting the criteria for euthanasia. 

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: The authors have responded to all my concerns. However a rebuttal letter with mentioning all the changes would be beneficial.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

In-vivo studies on Transitmycin, a potent Mycobacterium tuberculosis inhibitor

PONE-D-22-18915R2

Dear Dr. Dusthackeer,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: All my questions and comments were previously addressed and I don't have any further questions regarding this manuscript.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

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