PONE-D-24-42309Synthesis of Novel N-Substituted β-Amino Acid Derivatives Bearing 2-Hydroxyphenyl Moieties as Promising Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive PathogensPLOS ONE

Dear Dr. Kavaliauskas,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Wagdy M. Eldehna, Ph.d

Academic Editor

PLOS ONE

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a) The make/source of the NMR instrument used in your study, as well as the magnetic field strength. For each individual experiment, please also list: the nucleus being measured; the sample concentration; the solvent in which the sample is dissolved and if solvent signal suppression was used; the reference standard and the temperature.

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c)The full integrated NMR spectrum, clearly labelled with the compound name and chemical structure.

We also strongly encourage authors to provide primary NMR data files, in particular for new compounds which have not been characterised in the existing literature. Authors should provide the acquisition data, FID files and processing parameters for each experiment, clearly labelled with the compound name and identifier, as well as a structure file for each provided dataset. See our list of recommended repositories here: https://journals.plos.org/plosone/s/recommended-repositories .

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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

Reviewer #3: Yes

Reviewer #4: Yes

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

Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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: Yes

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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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: Review “ Synthesis of Novel N-Substituted β-Amino Acid Derivatives Bearing 2-Hydroxyphenyl Moieties as Promising Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens“

Lines 51-53 Check citations. Enterococcus species or Enterococcus faecium? It is important.

Line 57 Check Enterococcus or Enterococcci or Enterococcus faecium. What do you mean “Enterococcus“?

Line 441 Check the name E. clocea or E. cloacae ? Write the full name of this pathogen when you mention it for the first time.

Line 442 Institute of Infectious Diseases and Pathogenic Microbiology collection. Where is it?

Line 446 What about fungal strains? It must be described.

Line 453 A producer of 96-well microplates is not mentioned.

Line 455 A producer of CAMHB is not mentioned.

Line 456 A producer of RMPI/MOPS media is not mentioned.

Line 463 “tested drug“ or tested compound?

Line 466 The control of antibacterial and antifungal agents is not described. The producers of antibiotics must be mentioned.

Line 521 You must write Enterococcus faecalis. Do not us Italic for spp. !

Line 522 spp. but not spp

Line 522 E. cloacae but not Enterobacter spp

Line 530 You used bacterial strains and isolates, but not only isolates. The title of the table 1 must be improved.

Table 1 Explain, what “128>“ means. You write “128>“ when the compound concentration of 128 mg/mL showed no antimicrobial activity and the higher concentration equal to 256 mg/mL was not tested. It would be better to write that the results were negative. “128 >“ is an interpretation of your results? In my opinion, the presentation of data in the table 1 is subject to discussion or correction. Furthermore, in the abstract, you write that “one of the compounds demonstrated activity against Gram-negative pathogens“.

Explain why MBCs of compounds were not determined.

Line 614 “Enterococcus species.,“? Check grammar! Isn‘t the member of ESKAPE group only Enterococcus faecium? Is E. faecalis also a member of ESKAPE group?

Line 678 Staphylococcus but not Staphylococcus

Line 684 “Collectively, in this study,“ The beginning of conclusions does not seem good.

Use Italic when it is required as writen in an attachent.

Reviewer #2: This manuscript is devoted to the development of new antimicrobial drugs. The relevance of this issue is undeniable and constant, since it is necessary to continuously update the pool of these drugs due to the resistance to active substances developed by pathogenic organisms. The authors focused their attention on N-substituted β-amino acid derivatives bearing a 2-hydroxyphenyl moiety, synthesizing a number of compounds containing this fragment and belonging to several very different classes of organic compounds, including heterocyclic ones. Having determined their activity in relation to several types of pathogenic microorganisms, they found that the substituted 1,3,4-oxadiazole-2(3H)-thione showed the greatest activity.

In this regard, I have a wish for the authors: it is worth discussing in more detail which fragment determines the activity in this case - β-amino acid or 1,3,4-oxadiazole-2(3H)-thione.

From a chemical point of view, the work is of particular interest in that the authors did not limit themselves to one or two reactions, but demonstrated the richness of organic synthesis and the diversity of chemical properties of carboxylic acids. Personally, I found it interesting to read the manuscript. The experiment was performed well. I have no doubts about the structure of the obtained compounds, since they are almost completely characterized, and the quality of the presented NMR spectra is quite high.

Several comments on the description of the results are given below:

1. In Scheme 3 and in the text that describes it, the initial dicarbonyl compounds (acetylacetone and acetonylacetone) are confused.

2. It would be very good if the authors could explain why in the 1H NMR spectra of dihydrazides 7-14 there are 3 signals of the phenol proton and 3-4 signals of the NH protons, while in the 13C NMR spectra of some of these compounds there are 2 signals of carbonyl carbon atoms. There are two questions here: a) why are there several signals at all, despite the apparent symmetry of these compounds; b) why the number of forms according to 1H and 13C NMR data is sometimes different? It is desirable to add a discussion of this fact to the discussion section devoted to these compounds.

3. In the description of the fluorine-substituted derivative (compound 8), the 19F NMR spectrum should be added, and either the signals of carbon atoms with C-F coupling constants should be indicated, or the spectrum with fluorine decoupling should be registered. Currently, the 13C NMR spectrum does not formally correspond to the proposed structure, since it contains 29 signals of aromatic protons, which exceeds all reasonable limits.

4. The description of the synthetic methods contains many typos and language errors. For example, in the description of the synthesis of compound 3, for some reason, the present tense is used instead of the past tense, as in the description of compound 2 (and as it should be). Moreover, this is far from the only example of a tense discrepancy, sometimes even within a single sentence. Examples of other inaccuracies (not exhaustive):

- Line 138. "the reaction mixture 20 minutes stirred" should be changed to "the reaction mixture was stirred for 20 minutes".

- Line 154. "the residuse neutralized" should be changed to "the residue was neutralized".

The authors should proofread this section more carefully.

Reviewer #3: - The study has been well designed, organized, worked and prepared. The topic is important and actual. It seems the continuation of the previous work (ref.28) in order to investigate and compare the effects of the (various) substituent groups in different positions on the drug-resistant patogens.

- In the results part, H-NMR values are in 2 decimals, but also C-NMR values are in 2 decimals. However, the C-NMR values should be written in 1 decimal in a scientific paper.

- In some H-NMR and C-NMR results, the numbers of protons and carbons are inconsistent with the spectra/structures, this should be checked.

- There are some additional/extra peaks for the H-NMR and C-NMR results, are they impurities? All purifications in the work were performed by crystallization/crystals and any other methods (e.g. column chromatography) were apply to purify the compounds, was this enough for a good purification? Because, especially for the biological activity tests purity/impurities are of high importance.

- Mass spectroscopy analyses are present for some compounds, not for all, is there a specific reason for that?

- Are the synthesized compounds new? If yes, this was not really emphasized in the manuscript and abstract, this is important and should be mentioned in the appropriate parts of the manuscript. If no, then the related references must be given.

- The preparation purposes of nearly all compound were well explained in the synthesis part except compound-6. It should also be mentioned in this part.

- Between the lines 582 and 603, the same issue was discussed and repeated twice, this should be checked and rearranged.

- Line 693: resistant; twice.

Reviewer #4: The article entitled “Synthesis of Novel N-Substituted β-Amino Acid Derivatives Bearing 2-Hydroxyphenyl Moieties as Promising Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens” describes the synthesis and biological evaluation of N-Substituted β-Amino Acid Derivatives with a 2-hydroxyphenyl moeity as the antimicrobial agents. The manuscript would be of general interest to the researchers of this field. Before recommending for publication, the authors should consider and incorporate in the present form of the manuscript of some concerns and comments that need to be addressed.

Some comments and corrections for authors:

1. Overally, the manuscript has some punctuation and grammatical errors and needs to be corrected (i.e., there must be comma before and in all mns when mention about over two parameters). Please run throughout the mns.

2. A figure showing the importance of N-substitution in β-amino acids in med chem from literature should be added to the intro section.

3. The reaction pathway is clear. But some of compounds were not fully characterized. Some molecules do not have FTIR analysis, others do not have HRMS analysis.

4. The authors must define the unknow/known compounds in the mns.

5. I’d prefer to see the X-ray single analyses of unexpected products such as 3, 6, and 24.

6. “ml” must be corrected as “mL”. Please check and correct throughout the mns.

7. The data of carbon NMR values should be one decimal after point.

8. I strongly recommend to the authors to support their findings with in silico methods and further studies such as time-kill assay and/or biofilm formation especially for 9 and 26.

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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

Reviewer #3: No

Reviewer #4: No

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Attachments

Attachment

Submitted filename: Review20240930.PONE-D-24-42309.docx

PONE-D-24-42309R1Synthesis of Novel N-Substituted β-Amino Acid Derivatives Bearing 2-Hydroxyphenyl Moieties as Promising Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive PathogensPLOS ONE

Dear Dr. Kavaliauskas,

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 Jan 10 2025 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,

Wagdy M. Eldehna, Ph.d

Academic Editor

PLOS ONE

Additional Editor Comments:

Dear Authors,

I hope this message finds you well. Upon reviewing your recent submission, I noticed that you have addressed the comments from only one reviewer. This may have been an oversight, and I want to ensure that all feedback is considered.

To proceed, please upload your responses to all reviewers' comments. If you do not provide a comprehensive response, I regret to inform you that the paper will be at risk of rejection.

Thank you for your attention to this matter.

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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)

Reviewer #4: (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: No

Reviewer #4: Yes

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

Reviewer #2: (No Response)

Reviewer #4: Yes

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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: (No Response)

Reviewer #4: 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: (No Response)

Reviewer #4: Yes

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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: None of my comments were taken into account. Therefore, I recommend that this manuscript be rejected.

Reviewer #4: I could not see the "rebuttal letter" for my comments and recommendations. In this case, I am sorry that the mns should be rejected because authors have not addressed my comments.

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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

Reviewer #4: 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.

Synthesis of Novel N-Substituted β-Amino Acid Derivatives Bearing 2-Hydroxyphenyl Moieties as Promising Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens

PONE-D-24-42309R2

Dear Dr. Kavaliauskas,

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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager®  and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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,

Wagdy M. Eldehna, Ph.d

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

Reviewer #4: 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

Reviewer #4: Yes

**********

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

Reviewer #2: Yes

Reviewer #4: 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: (No Response)

Reviewer #4: 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

Reviewer #4: 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: (No Response)

Reviewer #4: The study has been well designed, organized, and well prepared according to the reviewers' comments. The manuscript can be accepted.

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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

Reviewer #4: No

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