Structural Innovations in Vancomycin: Overcoming Resistance and Expanding the Antibacterial Spectrum

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript, entitled “Structural Innovations in Vancomycin: Overcoming Resistance and Expanding the Antibacterial Spectrum,” is generally well-written and adequately referenced. However, several aspects need improvement before it can be considered for publication.

 

a) The abstract is too extended and does not clearly reflect what the authors aim to describe. It should highlight the significance and contribution of this review article.

b) In the main body of the manuscript, the authors should clarify, among the various reports on the synthesis of vancomycin analogues and derivatives, what the specific contribution or importance of this review is.

c) The authors are encouraged to include figures and schemes within each section to make the reading more dynamic and engaging. Each section should be supported with appropriate visual representations.

d) A figure summarizing the structural modifications made to vancomycin over time should be included to provide a visual overview of the chemical evolution of the molecule.

e) It is important to distinguish between derivatives and analogues. The authors should define and clearly differentiate these terms, and use schemes or figures to illustrate the structural modifications (i.e., derivatives) and the analogues that have been synthesized, indicating whether they are structural analogues, functional analogues, or other types.

f) The authors should also explain the concept of semisynthetic derivatives and provide a brief description of the semisynthetic approaches used to obtain them.

g) The discussion and conclusion sections should be reconsidered, as they currently overlap. The authors could use the conclusion to offer synthetic perspectives, such as the potential for further structural modifications to generate new derivatives. The importance of synthesizing structural analogues of vancomycin should also be emphasized. Generally, the conclusions are unclear.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

 

This review paper provides a comprehensive summary and synthesis of recent advancements in vancomycin structural modifications aimed at overcoming antimicrobial resistance (AMR). The authors also cover seven analogs/analog groups that expand the antibacterial spectrum. The references have covered recent literatures. Overall, this review offers valuable summary and insights for medicinal chemists and other researchers.

 

 

Major:

1. General: please provide a vanomycin structure and indicate the modifications (sugar moieties, side chains, and the core) with corresponding improvements. The authors may map modifications around the structure. This figure could help audience visualize the SAR.
2. Section 4: please add at least one compound-target docking result to show the structure change that benefits the drug-protein interaction.

 

Minor:

1. Section 4: Please provide quantitative data, for instance, docking scores and binding energies, for key examples.  
2. Section 7: please make this section less generic. Please provide 1-2 future research priorities.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The work presented by Carrillo-Bestagno et al. extensively covers significant structural variations of vancomycin that have been carried out over the last few years. The report is well-written, with each section effectively addressing key information and offering concise yet crucial discussions. However, to meet the criteria of a scientifically sound review article, it needs further corrections and refinement, which will help enhance the quality and standards. Therefore, I recommend a major revision. I suggest that the authors improve and revise the manuscript by providing a point-by-point response to the comments outlined below.

Minor comments:

In the abstract: Remove abbreviations like MRSA and VRE from the abstract and rephrase the sentence. For example, "challenged by resistance in several strains of Staphylococcus aureus and Enterococcus spp." Correct Dipi-Van-Zn (line 19) as Dipi-Van-Zn⁺² and throughout the manuscript. Also, remove PBPK from line 28 and line 256 as it is used only once in the main text.

The author should mention the phrase "first-generation glycopeptide" when referring to vancomycin for the first time in the text.

In the introduction section, I suggest the author include the chemical structure of vancomycin and mention names of important structural components and/or common modification points of vancomycin discussed in the manuscript. Also, include structures of other vancomycin semi-synthetic and synthetic derivatives discussed in this manuscript. In these structures, highlight most important modification. For example, check reference 16 for the same.

Line 52: The word "Amycolatopsis orientalis" in this sentence should be written in italics. Similarly, in line 99, please correct it.

Line 57: "Staphylococcus aureus" should be written in italics throughout the manuscript. As a standard rule in biological nomenclature, genus and species names (binomial nomenclature) are always written in italics. So, I suggest correcting the style of other bacterial strain names. However, names of groups above the genus level (e.g., family, order, class) are not written in italics. For example, Enterococci is correctly mentioned (line 56) in the manuscript.

Line 69: I suggest the authors mention approval years for the semisynthetic derivatives. Also, in the same sentence, add the phrase "second-generation lipoglycopeptides" at the appropriate place.

Maintain uniform writing for common words. For example, in line 130 it says beta-lactam antibiotics, but in line 155 it is written as β-lactam antibiotics. Also, "β" should be written in italics; check the same elsewhere in other words.

Line 135: Provide the full name of scientific societies and remove their abbreviations or else just remove all abbreviations.

Line 137: Mention the abbreviation VISA in brackets at the appropriate place. Also, mention the full name of VRSA and put the abbreviation in brackets.

Lines 171-179: I suggest merging this paragraph with the above ones.

Line 177: In N-methyl-leucine, "N" should be written in italics. Also, check elsewhere in the text.

Line 191: The word "in vitro" should be written in italics. Also, check elsewhere in the text.

Lines 226-229: From line 229, remove the phrase "a semi-synthetic lipoglycopeptide" and insert it in lines 226-227. For example, "Clinically approved semi-synthetic lipoglycopeptides illustrate the success of these strategies."

Line 300: In >88 μM, put a space between ">" and "88".

Line 333: Remove the text "featuring an additional functional group at the C-terminal (C80H87C12N11O24)" from here as it is for the discussion section where it is already mentioned.

Lines 336-339: I suggest citing reference 37 here.

Line 399: Remove the full name of LPS from here as it is already mentioned in line 295.

Author should mention or cite work carried out by Boger team as reported in Proc Natl Acad Sci U S A 2017 Jun 27;114(26):E5052-E5061. doi: 10.1073/pnas.1704125114.

(check   https://doi.org/10.1073/pnas.170412511)

Major comments:

1. Since this review deals with "Structural Innovations in Vancomycin," I suggest the author provide a comparison table of structural modification sites/strategic alterations and key benefits of derivatives, such as oritavancin, dalbavancin, and telavancin over the parent drug vancomycin. Also, do the same for other derivatives discussed in the manuscript.
2. Lines 186-219: This part needs slightly rearranged text and clearer mention of where modifications are done, and such information should appear as per the pattern written in lines 188-189. For Vanc-83, it is mentioned that modification is done at the C-terminus but not for Vanc-42. Also, information mentioned in lines 202-206 can be moved after the Vanc-42 text. In this section, information regarding the homo- and heterodimers is missing. Could it be reference 52? Information regarding conjugating vancomycin derivatives needs to be in one place. For example, conjugation of vancomycin with antimicrobial peptides (AMPs), Zinc (II), and vancomycin-peptide conjugates (VPCs) discussed in this section.
3. Dalbavancin discussed in the manuscript is not a semisynthetic derivative of vancomycin—it is a semisynthetic derivative of teicoplanin-like glycopeptides. However, it is closely related to vancomycin. So, I suggest the author remove this semisynthetic derivative-related discussion from the text or justify its inclusion by making appropriate changes to the text.
4. I suggest adding a comparison table related to main resistance genes, strains, target mutation/modification, and outcome (low or high resistance, etc.) for better clarity to the reader.
5. Some of the given information needs further refinement. For example, in line 229, it says dalbavancin exhibits an exceptionally long half-life. So please clarify the same by mentioning its value. In line 327, for oritavancin, the author should mention the volume of distribution in L/kg for better comparison with other lipoglycopeptides and other derivatives. In line 330, for telavancin, the author should mention typical clinical dose information. To provide a better overview, I suggest the author include a comparison table of main key pharmacokinetic and dosing parameters (i.e., typical clinical dose, Cmax, Half-life (t₁/₂), and volume of distribution (Vd)) of derivatives, such as oritavancin, dalbavancin, and telavancin (and others) with the parent drug vancomycin.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

All the suggestions provided in the first revision have been carefully addressed by the authors. The revised manuscript incorporates the necessary corrections, including improved structure, content clarification, and the addition of relevant figures and discussions. In its current form, the article meets the journal's standards and is ready for publication.

Author Response

Thank you for your comment.

Reviewer 3 Report

Comments and Suggestions for Authors

I suggest to carryout minor update as suggested below before acceptance.

Line 31: Replace the word "ongoing" with "previously carried out" and refine the sentence if needed.

Figure 1: Use the PNG file format for better clarity regarding all chemical structures.

Table 1: In the abbreviations section, ensure that the names of bacterial strains are italicized for proper scientific formatting.

Author Response

I suggest to carryout minor update as suggested below before acceptance.

Line 31: Replace the word "ongoing" with "previously carried out" and refine the sentence if needed.

R: Thank you for the suggestion, we have made the correction.

Figure 1: Use the PNG file format for better clarity regarding all chemical structures.

R: Thank you for the suggestion, the image is already in PNG format.

Table 1: In the abbreviations section, ensure that the names of bacterial strains are italicized for proper scientific formatting.

R: Thank you for the suggestion, we have made the corrections.