Dear Ms Budak,

Thank you very much for submitting your manuscript "Optimizing tuberculosis treatment efficacy: comparing the standard regimen with Moxifloxacin-containing regimens" for consideration at PLOS Computational Biology. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

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Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Adrianne L Jenner

Academic Editor

PLOS Computational Biology

Amber Smith

Section Editor

PLOS Computational Biology

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A link appears below if there are any accompanying review attachments. If you believe any reviews to be missing, please contact ploscompbiol@plos.org immediately:

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: This is a very well written manuscript that integrates computational and experimental approaches to advance the field of TB therapeutics, by addressing some of the hardest problems in the field, reducing treatment duration and optimizing dose. I'm attaching some questions below for the authors to provide written response back on and help improve the manuscript from the standpoint of the reader.

Line 169/170: Can the model be extended to predict relapse rate in patients after end of treatment ? Simulation results indicate one would expect a better outcome, but the translational results in the clinic indicate otherwise.

Line 243: What do you make of the differences between model and experimental results on metabolic effects of RMZE ?

Line 243: Are there markers of inflammation in the model and have these shown any results showing reduction in inflammation ?

Line 260: What other features of granulomas were varied in these simulations ? e.g. size, inflammatory, metabolic,…

Line 351: What PKPD information about each drug was used to do the dose predictions, and have you considered penetration depth ?

Discussion: Future work can consider testing a subset of the top functioning combinations in an animal model. Also consider expanding the model to include prediction of clinical relapse.

Reviewer #2: 1. Please clarify how did the authors derive adjusted concentration for 3 or 4 drug combinations?

2. With respect to the simulations with GranSim shown in Figure 6: As these were standard doses, and some of the combinations have been evaluated in literature in preclinical models, is there a similarity in trends for time to sterilization metric? Something like that could lend validity to the GranSim simulations.

3. Comparing GranSim simulations to NHP and humans (Figure 2,3): Does GranSim consider interspecies PK or PD parameter scaling, or differences in PD parameter within granulomas of the different species?

4. In Figure 1, Does each individual data point come from single NHP or multiple NHPs? Please elaborate?

5. With respect to Figure 5, what is the typical distribution of the ratio of high-low CFU granulomas observed clinically? Clinical relevance could add value.

6. When making the various comparisons, particularly in figures 2-6, provide a measure of how much change was observed along with a measure of variability and a statistic quantifying the differences.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: None

Reviewer #2: Yes

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Reviewer #1: Yes: Karim Azer

Reviewer #2: No

Figure Files:

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References:

Review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Dear Ms Budak,

We are pleased to inform you that your manuscript 'Optimizing tuberculosis treatment efficacy: comparing the standard regimen with Moxifloxacin-containing regimens' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology. 

Best regards,

Adrianne L Jenner

Academic Editor

PLOS Computational Biology

Amber Smith

Section Editor

PLOS Computational Biology

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Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: The authors have successfully addressed all comments and updated the manuscript as necessary. The manuscript represents strong computational science and will help advance the field of TB drug combination design and translation into the clinic.

Reviewer #2: The authors have addressed all my comments and questions adequately.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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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: Yes: Karim Azer

Reviewer #2: No