Dear Dr. Toro-Navarro,

• 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'.
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We look forward to receiving your revised manuscript.

Kind regards,

Vasu D. Appanna

Academic Editor

PLOS ONE

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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?

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: The manuscript is scientifically sound, clearly written, and the modeling and analyses are applied appropriately. My comments focus on improving clarity, mainly separating experimental results from interpretation, explaining unusually high yield coefficients, and adding brief methodological detail to ensure reproducibility. These are minor revisions and do not affect the validity or significance of the work.

Reviewer #2: In this manuscript, the authors use experimental evidence in tandem with in silico analysis to model the growth of streptomyces clavuligerus in complex medium. Given its importance in producing the beta-lactamase inhibitor clavulanic acid, the authors suggest the data within can be used to generate genetically engineered bacteria to better generate this antibiotic.

The paper is sound. I have a few minor recommendations:

- Figure captions should include more details (n value and statistical analysis if applicable)

- Figure three is missing the x axis legend (Time in h)

- If the resolution on figure 5 can be improved, it would increase legibility

- Remove the image of a mitochondrion in Figure 7, which are not present in bacteria and thus misleading

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Reviewer comments- PONE-D-25-57065.docx

Dynamic metabolic modeling of Streptomyces clavuligerus in complex medium highlights nutrient-dependent metabolic transitions associated with clavulanic acid biosynthesis

PONE-D-25-57065R1

Dear Dr. Toro-Navarro,

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.

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Kind regards,

Vasu D. Appanna

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: All comments have been addressed. The revisions greatly enhance clarity and transparency, and no further changes are necessary from my side.

Reviewer #2: I have no further comments. The authors have responded to all my concerns. I believe the manuscript to be acceptable.

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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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